COPD TSLP

… thymic stromal lymphopoietin (TSLP) which has … TSLP in modulating ASM function in relationship with airway inflammation, bronchoconstriction and remodelling in asthma and COPD…

The airway epithelium, through pattern recognition receptors expressed transmembrane or intracellularly, acts as a first line of defense for the lungs against many environmental triggers. It is involved in the release of alarmin cytokines, which are important mediators of inflammation, with receptors widely expressed in structural cells as well as innate and adaptive immune cells. Knowledge of the role of epithelial cells in orchestrating the immune response and mediating the clearance of invading pathogens and dead/damaged cells to facilitate resolution of inflammation is necessary to understand how, in many chronic lung diseases, there is a persistent inflammatory response that becomes the basis of underlying pathogenesis. This review will focus on the role of pulmonary epithelial cells and of airway epithelial cell alarmins, in particular thymic stromal lymphopoietin (TSLP) and high mobility group box 1 (HMGB1), as key mediators in driving the inflammation of chronic lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), evaluating the similarities and differences. Moreover, emerging concepts regarding the therapeutic role of molecules that act on airway epithelial cell alarmins will be explored for a precision medicine approach in the context of pulmonary diseases, thus allowing the use of these molecules as possible predictive biomarkers of clinical and biological response.

BACKGROUND Macrophages are the predominant immune cells in the human lung and play a central role in airway inflammation, including asthma and chronic obstructive pulmonary disease (COPD). Thymic stromal lymphopoietin (TSLP), a pleiotropic cytokine mainly expressed by bronchial epithelial cells, plays a key role in asthma and COPD pathobiology. TSLP exists in two variants: the long form (lfTSLP) and a shorter TSLP isoform (sfTSLP). We aimed to localize TSLP in human lung macrophages (HLMs) and investigate the mechanisms of its release from these cells. We also evaluated the effects of the two variants of TSLP on the release of angiogenic factor from HLMs. METHODS We employed immunofluorescence and Western blot to localize intracellular TSLP in HLMs purified from human lung parenchyma. HLMs were activated by T2-high (IL-4, IL-13) and T2-low (lipopolysaccharide: LPS) immunological stimuli. RESULTS TSLP was detected in HLMs and subcellularly localized in the cytoplasm. IL-4 and LPS induced TSLP release from HLMs. Preincubation of macrophages with brefeldin A, known to disrupt the Golgi apparatus, inhibited TSLP release induced by LPS and IL-4. lfTSLP concentration-dependently induced the release of vascular endothelial growth factor-A (VEGF-A), the most potent angiogenic factor, from HLMs. sfTSLP neither activated nor interfered with the activating property of lfTSLP on macrophages. CONCLUSIONS Our results highlight a novel immunologic circuit between HLMs and TSLP. Given the central role of macrophages in airway inflammation, this autocrine loop holds potential translational relevance in understanding innovative aspects of the pathobiology of asthma and chronic inflammatory lung disorders.

Thymic stromal lymphopoietin (TSLP) is an alarmin cytokine activated by allergens, pathogens, and air pollutants. Recent studies suggest TSLP dysregulation in chronic inflammatory diseases. It was highlighted as a key player in the context of asthma‐associated mucosal immunity. This study investigated the production and localization of TSLP and its receptors in airway epithelial cells and the related inflammatory response in chronic obstructive pulmonary disease (COPD) and non‐COPD patients. TSLP transcripts and proteins were detected in epithelial cells but were not abundant at a steady state. The secretion of airway inflammatory mediators was altered in COPD in association with TSLP production. The cellular and molecular characterization of TSLP signaling may identify COPD patients that could benefit from anti‐alarmin therapeutic approaches.

Abstract A weighted genetic risk score (GRS) based on 16 SNPs implicated in reduced lung function in both Japanese and non-Japanese populations was previously associated with the onset of COPD and asthma. We here examine the genetic impact of this lung function GRS on specific COPD phenotypes. A cohort of Japanese COPD patients (N = 270) underwent lung function testing followed by genotyping with allele-specific arrays for 16 SNPs as well as expression quantitative trait loci at TSLP (rs2289276, rs3806933). Lung function GRS scoring and two-step cluster analyses grouped patients into different COPD phenotypes based on gender, age, smoking index, %FEV1 and lung function GRS. The genetic effect of TSLP on COPD phenotypes was also examined for interactions with the lung function GRS. A total of 270 participants were grouped into 5 clusters. The cluster with the highest levels of lung function GRS was characterized by moderate to severe airflow obstruction and the highest blood eosinophil counts. Regarding TSLP, an increased number of T alleles at both SNPs was found in the cluster characterized by moderate to severe airflow obstruction and heavy smoking (rs2289276, p value = 0.035; rs3806933, p value = 0.047) independent of the lung function GRS. A genetic susceptibility to impaired lung function carries an increased risk of developing COPD characterized by increased eosinophil counts and severe airflow obstruction while individuals with increased TSLP responses to external stimuli have an independent risk of developing severe airflow obstruction in the presence of heavy smoking.

Background. The cross-talk between the external and internal environment in the respiratory tract involves macrophage/dendritic cell (DC) transepithelial network. Epithelium triggers dendritic cell-mediated inflammation by producing thymic stromal lymphopoietin (TSLP), IL-33, and IL-17A. The study aimed to evaluate the expression of TSLP, IL-33, and IL-17A in human monocyte derived dendritic cells (moDCs) co-cultured with respiratory epithelium and monocyte derived macrophages (moMφs) in asthma, chronic obstructive pulmonary disease (COPD) and healthy controls. Methods. The study used a triple-cell co-culture model, utilizing nasal epithelial cells, along with moMφs and moDCs. Cells were cultured in mono-, di-, and triple-co-cultures for 24 h. Results. Co-culture with epithelium and moMφs significantly increased TSLP in asthma and did not change IL-33 and IL-17A mRNA expression in moDCs. moDCs from asthmatics were characterized by the highest TSLP mRNA expression and the richest population of TSLPR, ST2, and IL17RA expressed cells. A high number of positive correlations between the assessed cytokines and CHI3L1, IL-12p40, IL-1β, IL-6, IL-8, TNF in moDCs was observed in asthma and COPD. Conclusion. TSLP, IL-33, and IL-17A expression in moDCs are differently regulated by epithelium in asthma, COPD, and healthy subjects. These complex cell–cell interactions may impact airway inflammation and be an important factor in the pathobiology of asthma and COPD.

… of TSLP. This response is exaggerated in bronchial epithelial cells from asthmatic as well as chronic obstructive pulmonary disease (COPD) … inflammation, pulmonary TSLP was induced …

Thymic stromal lymphopoietin (TSLP) is a cytokine expressed in the epithelium, involved in the pathogenesis of chronic disease. IL-17A regulates airway inflammation, oxidative stress, and reduction of steroid sensitivity in chronic obstructive pulmonary disease (COPD). TSLP and IL-17A were measured in induced sputum supernatants (ISs) from healthy controls (HC), healthy smokers (HS), and COPD patients by enzyme-linked immunosorbent assay. Human bronchial epithelial cell line (16HBE) and normal bronchial epithelial cells were stimulated with rhIL-17A or ISs from COPD patients to evaluate TSLP protein and mRNA expression. The effects of the depletion of IL-17A in ISs, an anticholinergic drug, and the silencing of inhibitor kappa kinase alpha (IKKα) on TSLP production were evaluated in 16HBE cells. Coimmunoprecipitation of acetyl-histone H3(Lys14)/IKKα was evaluated in 16HBE cells treated with rhIL-17A and in the presence of the drug. TSLP and IL-17A levels were higher in ISs from COPD patients and HS compared with HC. TSLP protein and mRNA increased in 16HBE cells and in normal bronchial epithelial cells stimulated with ISs from COPD patients compared with ISs from HC and untreated cells. IKKα silencing reduced TSLP production in 16HBE cells stimulated with rhIL-17A and ISs from COPD patients. RhIL-17A increased the IKKα/acetyl-histone H3 immunoprecipitation in 16HBE cells. The anticholinergic drug affects TSLP protein and mRNA levels in bronchial epithelial cells treated with rhIL-17A or with ISs from COPD patients, and IKKα mediated acetyl-histone H3(Lys14). IL-17A/IKKα signaling induced the mechanism of chromatin remodeling associated with acetyl-histone H3(Lys14) and TSLP production in bronchial epithelial cells. Anticholinergic drugs might target TSLP derived from epithelial cells during the treatment of COPD. Two proteins involved in the maturation of immune cells contribute to the inflammation responsible for chronic obstructive pulmonary disease (COPD) and could thus provide promising drug targets for future therapies. Mirella Profita from the Institute of Biomedicine and Molecular Immunology “Alberto Monroy” in Palermo, Italy, and colleagues showed that lung secretions from people with COPD and those who smoke cigarettes have higher levels of interleukin-17A and thymic stromal lymphopoietin (TSLP), two proteins associated with inflammatory immune responses, than samples from healthy non-smokers. In bronchial epithelial cell lines, the researchers showed that interleukin-17A induces the expression of TSLP, whereas an existing bronchodilatator anticholinerc drug, usually used to treat COPD, reduces TSLP levels. The authors suggest that these drugs could complement existing COPD therapies to block proinflammatory proteins.

Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory condition with high morbidity and mortality. This study aimed to investigate the relationship between interleukin-33 (IL-33), thymic stromal lymphopoietin (TSLP), and eosinophilic granulocyte (EOS) levels and the treatment effect and exacerbation risk of COPD. A total of 225 COPD patients who were diagnosed and treated in our hospital from October 2021 to September 2024 were selected as the research objects for retrospective analysis and study, and were recorded as the COPD group. 200 subjects who underwent physical examination in our hospital at the same period were selected as the control group. The serum levels of IL-33, TSLP and EOS were compared between the two groups. The patients were divided into the effective group (102 cases) and the ineffective group (123 cases) according to the reduction of chronic obstructive pulmonary disease assessment test (CAT) score not less than 2 points or lung function grade not less than 1 grade after 1 week of treatment (considered effective). After a 12-month follow-up, patients were further divided into acute exacerbation (n = 104) and non-acute exacerbation (n = 121) groups according to the occurrence of acute exacerbation (patients’ clinical symptoms deteriorated beyond the daily range in a short period of time and needed to change treatment). The changes of serum IL-33, TSLP and EOS levels in patients with different treatment effects and exacerbation risks were detected. The receiver operating characteristic (ROC) curve was used to analyze the predictive value of serum IL-33, TSLP and EOS alone and in combination for the treatment effect and malignant risk of COPD. Multivariate Logistic regression was used to analyze the influencing factors of ineffective treatment and exacerbation in COPD patients. Patients with COPD showed higher serum IL-33 and EOS levels and lower TSLP compared to the control group (P < 0.05). Compared with the effective group, patients in the ineffective group showed significantly higher serum levels of IL-33 and EOS and a significantly lower level of TSLP (P < 0.05). Patients in the acute exacerbation group showed higher serum levels of IL-33 and EOS and a lower level of TSLP than the non-acute exacerbation group (P < 0.05). The area under the curve (AUC) of serum IL-33, TSLP, and EOS in detecting the treatment effect of COPD was 0.803, 0.778, and 0.870, respectively. The AUC of combined detection was 0.938, suggesting that the combined detection had a higher predictive value. The AUC for IL-33, TSLP, and EOS were 0.679, 0.716, and 0.891, respectively, with a combined detection AUC of 0.931. For the assessment of COPD exacerbation risk, the combined detection of three indicators had higher clinical value. Multivariate Logistic regression analysis showed that after adjusting for confounding factors such as age, sex, smoking status, and basic pulmonary function, elevated serum IL-33 and EOS levels were still independent risk factors for treatment failure (P < 0.05), while elevated TSLP level was a protective factor (P < 0.05). In terms of predicting the risk of acute exacerbation, the elevated EOS level was an independent risk factor (P < 0.001), and the independent predictive value of IL-33 and TSLP did not reach statistical significance (P > 0.05). The levels of IL-33 and EOS were significantly increased, and the level of TSLP was significantly decreased in patients with effective treatment and acute exacerbation of COPD. The above indicators could be used as important indicators to predict the treatment effect and malignant risk of COPD, and the combined detection had high sensitivity and specificity.

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and chronic airway inflammation, traditionally managed with inhaled bronchodilators and corticosteroids. However, a significant subset of patients exhibits suboptimal response to these inhaled therapies, and disease progression remains challenging to control effectively. Recent advances in understanding the inflammatory pathways underlying COPD have led to the development of biologic agents targeting critical cytokines and their receptors, including IL-4 receptor (IL-4R), IL-5, IL-5 receptor (IL-5R), IL-33, ST2, and thymic stromal lymphopoietin (TSLP). Emerging drugs such as JKN2401, TQC2731, and tezepelumab demonstrate promising therapeutic potential by modulating these specific inflammatory mediators. This review comprehensively summarizes the pathophysiological roles of these cytokines in COPD, the current progress in biologic drug development targeting these molecules, and the outcomes of recent clinical trials. By elucidating these novel therapeutic avenues, the article aims to provide a theoretical foundation and clinical guidance for precision medicine approaches in COPD management beyond conventional inhaled treatments.

Rationale: Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory disease with several endo-phenotypes and clinical presentations. COPD patients present with the ‘canonical’ neutrophilic inflammation as well as eosinophilic inflammation. The lungs from COPD patients show elevated levels of IL-13 and TSLP and these cytokines are involved in the disease pathogenesis. IL-13 promotes the activation and trafficking of type 2 inflammatory cells to the lungs, leading to airway remodeling and parenchymal destruction and emphysema. IL-13 also increases the expression of MUC5AC, a major component of airway mucus. TSLP produced by bronchial epithelial cells directly acts on eosinophils and ILC2s, as well as on dendritic cell antigen presentation and Th2 cell differentiation, thereby contributing to enhanced type 2 inflammation in COPD. Combined blockade of IL-13 and TSLP could be an effective therapeutic approach in COPD. Methods: We leveraged lung and epithelial-brushing transcriptomic data from the SPIROMICS cohort of COPD patients and analyzed the association between IL-13 and TSLP signature enrichment and clinical variables. With 61 epithelial-brushing RNA-seq samples from SPIROMICS, we performed Gene Set Variation Analysis (GSVA) to calculate enrichment scores of IL-13 and TSLP signatures and tested their associations with over 200 clinical and imaging variables. Results: IL-13 and TSLP gene-signatures were negatively correlated with lung function, patients with highly expressed IL-13/TSLP signatures have lower slow vital capacity (SVC) and forced vital capacity (FVC). IL-13 and TSLP signatures were highly co-expressed and enriched in patients with blood eosinophil counts (BEC) ≥ 150 as well as BEC ≥ 300. 84.6% of patients with BEC ≥ 150 were enriched for IL-13/TSLP signatures, as compared to 59.1% in patient subset with BEC &amp;lt; 150 (p-value = 0.059). A threshold of BEC ≥ 150 includes 2.5-fold more patients than BEC ≥ 300, which greatly expands patient subset. Severe COPD patients (GOLD III &amp; IV) were enriched for IL-13/TSLP signatures with an odds ratio of 2.83 (p-value = 0.002). Smoking status of patients did not impact the enrichment of the IL-13/TSLP signatures. Conclusions: These findings provide a strong rationale for combined targeting of IL-13 &amp; TSLP in COPD in patients with a BEC threshold of ≥150.

INTRODUCTION Alarmins ((IL-25, IL-33 and thymic stromal lymphopoietin (TSLP)) are known to promote Th2 inflammation and could be associated with eosinophilic airway infiltration. They may also play a role in airway remodeling in chronic airway obstructive diseases such as asthma and chronic obstructive pulmonary disease (COPD). IL-23 and IL-36 were shown to mediate the neutrophilic airway inflammation as seen in chronic airway obstructive diseases. OBJECTIVES The purpose of this project was to determine the expression and the production of these cytokines from induced sputum (IS) in patients with chronic airway obstructive diseases including asthmatics and COPD. The relationship of the mediators with sputum inflammatory cellular profile and the severity of airway obstruction was assessed. METHODS The alarmins (IL-25, IL-33 and TSLP) as well as IL-23 and IL-36 concentrations were measured in IS from 24 asthmatics and 20 COPD patients compared to 25 healthy volunteers. The cytokines were assessed by ELISA in the IS supernatant and by RT-qPCR in the IS cells. RESULTS At protein level, no difference was observed between controls and patients suffering from airway obstructive diseases regarding the different mediators. IL-36 protein level was negatively correlated with sputum eosinophil and appeared significantly decreased in patients with an eosinophilic airway inflammation compared to those with a neutrophilic profile and controls. At gene level, only IL-36, IL-23 and TSLP were measurable but none differed between controls and patients with airway obstructive diseases. IL-36 and IL-23 were significantly increased in patients with an neutrophilic inflammatory profile compared to those with an eosinophilic inflammation and were correlated with sputum neutrophil proportions. None of the mediators were linked to airway obstruction. CONCLUSIONS The main finding of our study is that patients with eosinophilic airway inflammation exhibited a reduced IL-36 level which could make them more susceptible to airway infections as IL-36 is implicated in antimicrobial defense. This study showed also an implication of IL-36 and IL-23 in airway neutrophilic inflammation in chronic airway obstructive diseases.

Chronic obstructive pulmonary disease (COPD) is a main global epidemic increasing as population age and affecting approximately 10% of subjects over 45 years. COPD is a heterogeneous inflammatory disease with several endo-phenotypes and clinical presentations. Although neutrophilic inflammation is canonically considered a hallmark of COPD, eosinophilic inflammation can also be present in a subgroup of patients. Several other immune cells and cytokines play a key role in orchestrating and perpetuating the inflammatory pathways in COPD, making them attractive targets for treating this disorder. Recent studies have started to evaluate the possible role of type 2 (T2) inflammation and epithelial-derived alarmins (TSLP and IL-33) in COPD. Two phase III randomized clinical trials (RCTs) showed a modest reduction in exacerbations in COPD patients with eosinophilic phenotype treated with mepolizumab (anti-IL-5) or benralizumab (anti-IL-5Rα). A phase III RCT showed a 30% reduction in exacerbations in COPD patients with ≥ 300 eosinophils/μL treated with dupilumab (anti-IL-4Rα). These results suggest that blocking a single cytokine (e.g., IL-5) or its main target (i.e., IL-5Rα) is less promising than blocking a wider spectrum of cytokines (i.e., IL-4 and IL-13) in COPD. TSLP and IL-33 are upstream regulators of T2-high and T2-low immune responses in airway inflammation. Several ongoing RCTs are evaluating the efficacy and safety of anti-TSLP (tezepelumab), anti-IL-33 (itepekimab, tozorakimab), and anti-ST2 (astegolimab) in patients with COPD, who experience exacerbations. In conclusion, targeting T2 inflammation or epithelial-derived alarmins might represent a step forward in precision medicine for the treatment of a subset of COPD.

… TSLP might play a part in COPD and particularly COPD exacerbations. Therefore, blocking TSLP and TSLP-mediated signalling with anti-TSLP … a useful therapeutic approach for COPD. …

RATIONALE: Asthma and chronic obstructive pulmonary disease (COPD) are persistent inflammatory airway disorders characterized by obstructive airflow limitation, imposing a substantial burden on both patients and healthcare systems. Alarmins IL33 and TSLP have been established as validated therapeutic targets for the treatment of asthma and COPD. Notably, IL33 and TSLP are the only targets that have demonstrated clinical efficacy in non-Th2 asthma settings. Here we engineered and produced HXN-1013, a bispecific antibody (bsAb) simultaneously targeting both TSLP and IL33, with the aim to further enhance clinical efficacy for the treatment of asthma and COPD patients. METHODS: anti-TSLP antibodies were generated, characterized and selected through various in vitro assays, including TSLPR-STAT5-Luc reporter assays, TSLP-induced Baf3 proliferation, and CCL17 release from PBMCs. IL33 antibodies were generated and assessed using IL33 reporter assay, and L33 induced PBMC activation assay. The synergistic effect of dual targeting was measured by IL5 and IL13 release in human PBMCs co-stimulated with TSLP and IL33. RESULTS: Multiple anti-TSLP antibodies were generated with high potency and different binding epitopes, including antibodies targeting TSLP Site I (TSLPR binding site), Site II (IL7Rα binding site), and biparatopic antibodies that simultaneously targeting both site I and II. In TSLPR/STAT5 reporter assays and BaF3 proliferation assays, these antibodies demonstrated a significant activity advantage compared to Tezepelumab. We produced a number of anti-IL33 antibodies with superior potency compared to Itepekimab based on IL33 reporter assays and PBMC activation assays. Based on these building blocks, we engineered a bispecific antibody, HXN-1013, that is capable of simultaneously binding to both TSLP and IL33 and blocking the cytokines from interacting with it respective receptor. Each arm of the bsAb demonstrated a biological activity comparable to the parental antibodies. In the PBMC activation assay induced by both TSLP and IL33, the bsAb showed superior activity than each of the individual parent antibodies. CONCLUSIONS: HXN-1013 simultaneously blocks TSLP and IL33, with each arm exhibiting activity comparable to the parent antibodies. HXN-1013 has great potential to enhance clinical efficacy for the treatment of asthma and COPD.

… Objectives: Since COPD pathogenesis is characterized by airway … of TSLP and its receptor CRL2 in the pulmonary cell populations in bronchi and bronchioles of COPD and non-COPD …

… TSLP in chronic obstructive pulmonary disease (COPD) is less clear, although its expression at the mRNA and protein level is elevated in COPD (… TSLP protein in the BAL fluid of COPD …

Interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) are alarmins that are released upon airway epithelial injury from insults such as viruses and cigarette smoke, and play critical roles in the activation of immune cell populations such as mast cells, eosinophils and group 2 innate lymphoid cells. Both cytokines were previously understood to primarily drive type 2 (T2) inflammation, but there is emerging evidence for a role for these alarmins to additionally mediate non-T2 inflammation, with recent clinical trial data in asthma and COPD cohorts with non-T2 inflammation providing support. Currently available treatments for both COPD and asthma provide symptomatic relief with disease control, improving lung function and reducing exacerbation rates; however, there still remains an unmet need for further improving lung function and reducing exacerbations, particularly for those not responsive to currently available treatments. The epithelial cytokines/alarmins are involved in exacerbations; biologics targeting TSLP and IL-33 have been shown to reduce exacerbations in moderate-to-severe asthma, either in a broad population or in specific subgroups, respectively. For COPD, while there is clinical evidence for IL-33 blockade impacting exacerbations in COPD, clinical data from anti-TSLP therapies is awaited. Clinical data to date support an acceptable safety profile for patients with airway diseases for both anti-IL-33 and anti-TSLP antibodies in development. We examine the roles of IL-33 and TSLP, their potential use as drug targets, and the evidence for target patient populations for COPD and asthma, together with ongoing and future trials focused on these targets. Therapies targeting the alarmins IL-33 and TSLP form the next frontier for airway diseases. In addition to their role in adaptive immunity, emerging clinical data indicate these alarmins modulate innate immunity to address unmet needs in COPD and asthma. https://bit.ly/3tD8VM5

Asthma and chronic obstructive pulmonary disease (COPD) are associated with Th2 and Th1 differentiated T cells. The cytokine thymic stromal lymphopoietin (TSLP) promotes differentiation of Th2 T cells and secretion of chemokines which preferentially attract them. We hypothesized that there is distinct airways expression of TSLP and chemokines which preferentially attract Th1- and Th2-type T cells, and influx of T cells bearing their receptors in asthma and COPD. In situ hybridization, immunohistochemistry, and ELISA were used to examine the expression and cellular provenance of TSLP, Th2-attracting (TARC/CCL17, MDC/CCL22, I-309/CCL1), and Th1-attracting (IP-10/CXCL10, I-TAC/CXCL11) chemokines in the bronchial mucosa and bronchoalveolar lavage fluid of subjects with moderate/severe asthma, COPD, and controls. Cells expressing mRNA encoding TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10, but not I-TAC/CXCL11 and I-309/CCL1, were significantly increased in severe asthma and COPD as compared with non-smoker controls (p &amp;lt; 0.02). This pattern was reflected in bronchoalveolar lavage fluid protein concentrations. Expression of the same chemokines was also increased in ex- and current smokers. The cellular sources of TSLP and chemokines were strikingly similar in severe asthma and COPD. The numbers of total bronchial mucosal T cells expressing the chemokine receptors CCR4, CCR8, and CXCR3 did not significantly differ in asthma, COPD, and controls. Both asthma and COPD are associated with elevated bronchial mucosal expression of TSLP and the same Th1- and Th2-attracting chemokines. Increased expression of these chemokines is not, however, associated with selective accumulation of T cells bearing their receptors.

ABSTRACT Introduction Chronic obstructive pulmonary disease (COPD) is a disorder characterized by a complicated chronic inflammatory response that is resistant to corticosteroid therapy. As a result, there is a critical need for effective anti-inflammatory medications to treat people with COPD. Using monoclonal antibodies (mAbs) to inhibit cytokines and chemokines or their receptors could be a potential approach to treating the inflammatory component of COPD. Areas covered The therapeutic potential that some of these mAbs might have in COPD is reviewed. Expert opinion No mAb directed against cytokines or chemokines has shown any therapeutic impact in COPD patients, apart from mAbs targeting the IL-5 pathway that appear to have statistically significant, albeit weak, effect in patients with eosinophilic COPD. This may reflect the complexity of COPD, in which no single cytokine or chemokine has a dominant role. Because the umbrella term COPD encompasses several endotypes with diverse underlying processes, mAbs targeting specific cytokines or chemokines should most likely be evaluated in limited and focused populations.

… airway inflammation via TSLP-dependent pathway. chronic obstructive pulmonary disease (… COPD is characterized by chronic inflammation in the airway lumen along with increased …

&lt;i&gt;Background:&lt;/i&gt; Rhinovirus (RV)-induced chronic obstructive pulmonary disease (COPD) exacerbations exhibit TH&lt;sub&gt;2&lt;/sub&gt;-like inflammation. We hypothesized that RV-infected bronchial epithelial cells (BEC) overproduce TH&lt;sub&gt;2&lt;/sub&gt;-switching hub cytokine, thymic stromal lymphopoietin (TSLP) in COPD. &lt;i&gt;Methods:&lt;/i&gt; Primary BEC from healthy (HBEC) and from COPD donors (COPD-BEC) were grown in 12-well plates, infected with RV16 (0.5–5 MOI) or stimulated with agonists for either toll-like receptor (TLR) 3 (dsRNA, 0.1–10 µg/ml) or RIG-I-like helicases (dsRNA-LyoVec, 0.1–10 µg/ml). Cytokine mRNA and protein were determined (RTqPCR; ELISA). &lt;i&gt;Results:&lt;/i&gt; dsRNA dose-dependently evoked cytokine gene overproduction of TSLP, CXCL8 and TNF-α in COPD-BEC compared to HBEC. This was confirmed using RV16 infection. IFN-β induction did not differ between COPD-BEC and HBEC. Endosomal TLR3 inhibition by chloroquine dose-dependently inhibited dsRNA-induced TSLP generation and reduced generation of CXCL8, TNF-α, and IFN-β. Stimulation of cytosolic viral sensors (RIG-I-like helicases) with dsRNA-LyoVec increased production of CXCL8, TNF-α, and IFN-β, but not TSLP. &lt;i&gt;Conclusions:&lt;/i&gt; Endosomal TLR3-stimulation, by dsRNA or RV16, induces overproduction of TSLP in COPD-BEC. dsRNA- and RV-induced overproduction of TNF-α and CXCL8 involves endosomal TLR3 and cytosolic RIG-I-like helicases and so does the generation of IFN-β in COPD-BEC. RV16 and dsRNA-induced epithelial TSLP may contribute to pathogenic effects at exacerbations and development of COPD.

Background : Emphysema is one of the features of chronic obstructive pulmonary disease (COPD) and contributes to irreversible airflow limitation. Thymic stromal lymphopoietin (TSLP) which is a critical upstream cytokine inducing type 2 inflammation was found to be increased in the airway epithelium of COPD patients. But the role of TSLP in COPD, which is primarily associated with type I inflammation is not well-understood. Methods: TSLP receptor K/O mice and wild-type mice were bred in-house and housed in SPF facility in ventilated cages. Mice at different ages 2, 4, 6 and 12 months were examined for lung mechanics, lung function and lung volume using Flexivent FX System. Lungs were inflation fixed, embedded in paraffin and 5µ thick sections were stained with hematoxylin and eosin to assess lung inflammation and emphysematous changes. Total lung cells from 2, 4, 6, 9 and 12 weeks old mice were subjected to multicolor flow cytometry to identify different inflammatory and innate immune cells. Total lung homogenate supernatants were subjected to gelatin zymography to identify the matrix metalloprotease (MMP) activity. Expression of inflammatory cytokines was assessed by qPCR. Results: Compared to wild-type, TSLPR K/O mice showed increase in compliance and reduction in elastance starting from 4 months of age. These changes progressed with aging of mice and the mice showed extensive emphysema by histology and lung mechanics at 12 months of age. TSLPR K/O mice also showed reduced FEV0.2, and increase in lung volume and this change was statistically significant from WT mice at 6 months and beyond. Flow cytometry of CD45+ve lung cells indicated significant increases in neutrophils and Ly6clow monocytes/macrophage population. In addition, TSLPR K/O mice also showed increased MMP12 activity and expression of IFN-γ, CXCL9 and TNF-α. Conclusions: Our results indicate that TSLPR K/O mice spontaneously develop emphysema in an age-dependent manner and was associated with elevated MMP12 activity levels. Increase in the expression of TNF-α and IFN-γ, and infiltration of neutrophils and inflammatory monocytes/macrophages may indicate increased type I inflammation in TSLPR K/O mice. Our findings are unexpected, but novel indicating that TSLP may play a role in preventing/inhibiting progression of emphysema in COPD patients.

Highlights What are the main findings? We found an increased number of airway ILC2s expressing TSLP receptor and intracellular IL-5 in eosinophilic COPD patients compared with non-eosinophilic patients and heathy smokers. In COPD patients’ sputum, ILC2s correlated positively with sputum eosinophilia. What is the implication of the main finding? Our report suggests the involvement of ILC2s in airway eosinophilic inflammatory responses in COPD. Abstract Studies have shown that eosinophilic COPD (eCOPD) is a distinct phenotype of the disease. It is well established that innate lymphoid cells are involved in the development of eosinophilic inflammation. Interleukin(IL)-25, thymic stromal lymphopoietin (TSLP) and IL-33 are a group of cytokines produced by epithelium in response to danger signals, e.g., cigarette smoke, and potent activators of ILC2s. In the present study, we examined circulating and sputum ILC2 numbers and expression of intracellular IL-5 as well as receptors for TSLP, IL-33 and IL-25 by ILC2s in non-atopic COPD patients with and without (neCOPD) airway eosinophilic inflammation and healthy smokers. In addition, we examined the association between ILC2s and clinical indicators of COPD burden (i.e., symptom intensity and risk of exacerbations). ILC2s were enumerated in peripheral blood and induced sputum by means of flow cytometry. We noted significantly greater numbers of airway IL-5+ILC2s and TSLPR+ILC2s in eCOPD compared with neCOPD (p < 0.05 and p < 0.01, respectively) and HSs (p < 0.001 for both). In addition, we showed that IL-5+ILC2s, IL-17RB+ILC2s and ST2+ILC2s are significantly increased in the sputum of eCOPD patients compared with HSs. In all COPD patients, sputum ILC2s positively correlated with sputum eosinophil percentage (r = 0.48, p = 0.002). We did not find any significant correlations between sputum ILC2s and dyspnea intensity as measured by the modified Medical Research Council scale (mMRC) and symptom intensity measured by the COPD Assessment Test (CAT). These results suggest the involvement of epithelial alarmin-activated ILC2s in the pathobiology of eosinophilic COPD.

Thymic stromal lymphopoietin (TSLP), is a protein belonging to a class of epithelial cytokines commonly called alarmins, which also includes IL-25 and IL-33. Functionally, TSLP is a key player in the immune response to environmental insults, initiating a number of downstream inflammatory pathways. TSLP performs its role by binding to a high-affinity heteromeric complex composed of the thymic stromal lymphopoietin receptor (TSLPR) chain and IL-7Rα. In recent years, the important role of proinflammatory cytokines in the etiopathogenesis of various chronic diseases such as asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), chronic obstructive pulmonary diseases (COPDs), and chronic spontaneous urticaria has been studied. Although alarmins have been found to be mainly implicated in the mechanisms of type 2 inflammation, studies on monoclonal antibodies against TSLP demonstrate partial efficacy even in patients whose inflammation is not definable as T2 and the so-called low T2. Tezepelumab is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. Several clinical trials are evaluating the safety and efficacy of Tezepelumab in various inflammatory disorders. In this review, we will highlight major recent advances in understanding the functional role of TSLP, its involvement in Th2-related diseases, and its suitability as a target for biological therapies.

Thymic stromal lymphopoietin (TSLP) is an epithelial alarmin chiefly implicated in T2 airway inflammation, though it may also participate in broader (non-T2) inflammatory processes. The utility of airway epithelial gene expression of TSLP and its specific receptor subunit, cytokine receptor-like factor 2 (CRLF2), as biomarkers of downstream inflammation and clinical outcomes remains unclear. We analyzed RNA sequencing data from bronchial airway brushing obtained in phase 1 of the SPIROMICS bronchoscopy sub-study (N = 161: 23 never-smokers, 67 ever-smokers with COPD, 71 ever-smokers without COPD). We related airway TSLP and CRLF2 expression to clinical, hematologic/sputum measures, and gene-expression signatures of T2/eosinophilic and neutrophilic inflammation, including to our published T2 signature and to eosinophil and neutrophil signatures derived from single-cell atlas data. Associations used Spearman correlations and linear models adjusted for age, sex, race/ethnicity, COPD status, smoking status, and pack-years. CRLF2 expression correlated with gene-expression evidence of both T2/eosinophilic and neutrophilic inflammation: T2 signature (ρ = 0.26, p < 0.001), eosinophil signature (ρ = 0.44, p < 0.001), and neutrophil signature (ρ = 0.39, p < 0.001). CRLF2 was positively associated with log sputum neutrophil count (ρ = 0.24, p = 0.024) and blood neutrophil count (ρ = 0.036, p < 0.001), but not with sputum or blood eosinophil counts. Higher CRLF2 related to worse baseline lung function, particularly among current smokers, (lower post-bronchodilator FEV1: ρ = −0.21, p = 0.008), as well as greater 5-year FEV1 decline across current and former smokers (ρ = −0.22, p = 0.007). Significant findings persisted after covariate adjustment. In contrast, TSLP expression, although strongly correlated with expression of the epithelial alarmin IL33 (ρ = 0.53, p < 0.001), was negatively correlated with CRLF2 (ρ = −0.24, p = 0.002) and with eosinophil and neutrophil gene-expression signatures (ρ = −0.26 and −0.33, both p < 0.001). TSLP expression showed no association with sputum or blood cell counts. In bronchial epithelium from SPIROMICS, gene expression of CRLF2, but not of TSLP, tracked with downstream alarmin-relevant inflammatory programs, consistent with a regulatory role in TSLP signaling through TSLPR, as well as with clinically meaningful outcomes. CRLF2 expression was associated with evidence of both T2/eosinophilic and neutrophilic inflammation, and with lower baseline FEV1 and accelerated FEV1 decline, suggesting engagement of a broader, clinically relevant inflammatory milieu. By contrast, epithelial TSLP transcript levels mirrored IL33 gene expression but were not associated with cellular or transcriptomic inflammation. These findings position CRLF2, rather than TSLP expression itself, as a potential airway biomarker of TSLP-axis activity and disease impact with potential implications for patient stratification as well as strategic approaches for TSLP-pathway-targeted therapies. This abstract is funded by: SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C, 75N92024D00012), grants from the NIH/NHLBI (U01HL137880, U24HL141762, R01HL182622, R01HL144718, and R01HL093081), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from Amgen; AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Bristol Myers Squibb; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; Genentech; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; MGC Diagnostics; Novartis Pharmaceuticals Corporation; Nycomed GmbH; Polarean; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; Theravance Biopharma; Verona; and Mylan/Viatris.

Background Acute exacerbation in patients with chronic obstructive pulmonary disease (COPD) lacks reliable biomarkers. This study aimed to explore the predictive value of serum interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) for acute exacerbations of COPD (AECOPD). Methods This retrospective study included patients with stable-phase COPD between June 2023 and June 2024 at the Third Affiliated Hospital of Anhui Medical University. Patients were assigned to the low-risk and high-risk groups according to the number and severity of AECOPD events. Multivariable logistic regression analysis was used to identify the factors of AECOPD risk. Receiver operating characteristic (ROC) curves were used to assess the predictive value of IL-33 and TSLP for AECOPD risk. Results A total of 76 patients were enrolled, with 33 in the low-risk group and 43 in the high-risk group. Serum IL-33 (835.30 vs. 770.30, p = 0.008) and TSLP (102.20 vs. 90.45, p < 0.001) levels were higher in the high-risk group than in the low-risk group. Serum TSLP (odds ratio (OR) = 1.095, 95% confidence interval (CI): 1.013–1.184, p = 0.022) was independently associated with AECOPD. The area under the curve (AUC) for IL-33 in predicting AE was 0.677 (95%CI: 0.554–0.801), with 93.0% sensitivity and 39.4% specificity. The AUC for TSLP was 0.768 (95%CI: 0.659–0.878), with 76.7% sensitivity and 72.7% specificity. Combined prediction using IL-33 and TSLP yielded an AUC of 0.779 (95%CI: 0.669–0.888), with 81.4% sensitivity and 72.7% specificity. Conclusion High serum TSLP might be associated with an increased risk of AECOPD. While IL-33 alone showed high sensitivity and low specificity, its potential predictive value may be worth exploring.

Periostin and thymic stromal lymphopoietin (TSLP) are newly described markers of obstructive airway diseases and the mechanism by which both markers participate in immune response remains poorly understood. The aim of our study was to determine periostin and TSLP concentration in serum and induced sputum (IS) in patients with atopic asthma, chronic obstructive pulmonary disease (COPD), and controls, as well as to evaluate the potential link between periostin, TSLP, and Th2 immune response. Serum and IS levels of periostin, TSLP, IL-4, and IL-13 were determined in 12 atopic asthmatics, 16 COPD sufferers, and 10 controls. We noticed a significantly higher IS periostin and TSLP concentration at protein and mRNA level in asthmatics compared to the two other groups; additionally, periostin and TSLP were correlated positively with IS eosinophil count. A strong positive correlation between IS periostin and TSLP protein levels (r = 0.96) as well as mRNA expression level (r = 0.95) was found in patients with asthma. The results of our study show that periostin and TSLP are associated with eosinophilic airway inflammation and seem to be important drivers of atopic asthma but not COPD pathobiology. Very strong correlations between local periostin, TSLP, eosinophils, and IL-4 in asthma point to the link between periostin–TSLP and Th2 response.

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine originally isolated from a murine thymic stromal cell line. TSLP exerts its biological effects by binding to a high-affinity heteromeric complex composed of thymic stromal lymphopoietin receptor chain and IL-7Rα. TSLP is primarily expressed by activated lung and intestinal epithelial cells, keratinocytes, and fibroblasts. However, dendritic cells (DCs), mast cells, and presumably other immune cells can also produce TSLP. Different groups of investigators have demonstrated the existence of two variants for TSLP in human tissues: the main isoform expressed in steady state is the short form (sf TSLP), which plays a homeostatic role, whereas the long form (lfTSLP) is upregulated in inflammatory conditions. In addition, there is evidence that in pathological conditions, TSLP can be cleaved by several endogenous proteases. Several cellular targets for TSLP have been identified, including immune (DCs, ILC2, T and B cells, NKT and Treg cells, eosinophils, neutrophils, basophils, monocytes, mast cells, and macrophages) and non-immune cells (platelets and sensory neurons). TSLP has been originally implicated in a variety of allergic diseases (e.g., atopic dermatitis, bronchial asthma, eosinophilic esophagitis). Emerging evidence indicates that TSLP is also involved in chronic inflammatory (i.e., chronic obstructive pulmonary disease and celiac disease) and autoimmune (e.g., psoriasis, rheumatoid arthritis) disorders and several cancers. These emerging observations greatly widen the role of TSLP in different human diseases. Most of these studies have not used tools to analyze the expression of the two TSLP isoforms. The broad pathophysiologic profile of TSLP has motivated therapeutic targeting of this cytokine. Tezepelumab is a first-in-class human monoclonal antibody (1) that binds to TSLP inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety and efficacy. Several clinical trials are evaluating the safety and the efficacy of tezepelumab in different inflammatory disorders. Monoclonal antibodies used to neutralize TSLP should not interact or hamper the homeostatic effects of sf TSLP.

Th2 inflammation is associated with various characteristics of patients with chronic obstructive pulmonary disease (COPD). In this study, we analyzed the COPD exacerbation risk associated with serum levels of interleukin (IL)-25/thymic stromal lymphopoietin (TSLP) and eosinophils. We studied the KOCOSS cohort, a multicenter COPD cohort created by 54 medical centers in South Korea. We extracted data collected between April 2012 and August 2020. We measured serum levels of TSLP and IL-25 in those who agreed to provide blood, and assessed exacerbation risk according to each. In all, 562 patients were enrolled. The IL-25-high group had a lower St. George’s Respiratory Questionnaire score than others, and the TSLP-high group had a poorer exercise capacity than the TSLP-low group. There were no significant differences in the forced expiratory volume in 1 s (FEV1), the levels of Th2 inflammatory biomarkers, or the exacerbation histories between the two groups. The 3-year decline in FEV1 was not significantly affected by IL-25 or TSLP levels. In terms of 1-year exacerbation risk, individuals in the IL-25-high group were at lower risk for moderate-to-severe exacerbation than others. A high TSLP level was associated with a lower risk of severe exacerbation but only in the eosinophil-low group. Serum levels of IL-25 are negatively correlated with moderate-to-severe exacerbation risk in this cohort. A negative correlation between severe exacerbation risk and TSLP level was apparent only in the eosinophil-low group.

The cytokine thymic stromal lymphopoietin (TSLP) has pleiotropic functions beyond allergic diseases and T helper 2-type immune responses. Here, the authors highlight the roles of TSLP — beneficial or deleterious — in infectious disease, chronic inflammatory disease and cancer by acting on many different cell types. Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine that acts on multiple cell lineages, including dendritic cells, T cells, B cells, neutrophils, mast cells, eosinophils and innate lymphoid cells, affecting their maturation, survival and recruitment. It is best known for its role in promoting type 2 immune responses such as in allergic diseases and, in 2021, a monoclonal antibody targeting TSLP was approved for the treatment of severe asthma. However, it is now clear that TSLP has many other important roles in a variety of settings. Indeed, several genetic variants for TSLP are linked to disease severity, and chromosomal alterations in TSLP are common in certain cancers, indicating important roles of TSLP in disease. In this Review, we discuss recent advances in TSLP biology, highlighting how it regulates the tissue environment not only in allergic disease but also in infectious diseases, inflammatory diseases and cancer. Encouragingly, therapies targeting the TSLP pathway are being actively pursued for several diseases.

Thymic stromal lymphopoietin (TSLP) seems a promising asthma biomarker. In earlier studies, mainly the serum concentration of TSLP was investigated. The aim of the present study …

Thymic stromal lymphopoietin (TSLP) is a newly identified IL-7–like cytokine known to be expressed in airway biopsies of patients with asthma and chronic obstructive pulmonary disease. As both diseases may be induced or exacerbated by cigarette smoking, it is possible that TSLP represents an important link between cigarette smoke exposure and inflammatory signaling in the airways. In this regard, TSLP appears to also be expressed in airway smooth muscle (ASM); however, its role is unknown. In the current study, we examined TSLP and the TSLP receptor (TSLP-R) expression and function in human ASM cells under normal conditions and following exposure to cigarette smoke extract (CSE). Western blot analysis of human ASM cells showed significant expression of TSLP and TSLP-R, with increased expression of both by overnight exposure to 1 or 2% CSE. Furthermore, CSE increased TSLP release by ASM. In parallel experiments using enzymatically dissociated human ASM cells loaded with the Ca2+ indicator fura 2-AM and imaged using fluorescence microscopy, we evaluated the effects of CSE exposure on intracellular Ca2+ ([Ca2+]i) responses to agonist stimulation. [Ca2+]i responses to histamine were increased with overnight CSE exposure. Exposure to TSLP also resulted in elevated responses, which were blunted by TSLP and TSLP-R Abs. Importantly, the enhancing effects of CSE on [Ca2+]i responses were also blunted by these Abs. These effects were associated with CSE- and TSLP-induced changes in STAT5 phosphorylation. Overall, these novel data suggest that cigarette smoke, TSLP, and ASM are functionally linked and that cigarette smoke-induced increase in airway contractility may be mediated via ASM-derived increases in TSLP signaling.

… Tezepelumab received orphan drug designation for the … COPD, CRSwNP and chronic spontaneous urticaria. This article summarizes the milestones in the development of tezepelumab …

Rationale: Tezepelumab is a human monoclonal antibody … severe COPD were randomized 1: 1 to receive tezepelumab 420 … had≥ 2 moderate or severe COPD exacerbations in the 12 …

… Previous monoclonal antibody therapies for COPD have targeted neutrophilic inflammatory … efficacy and safety of tezepelumab in COPD ( 1 ). In asthma, tezepelumab has been shown …

… 3 clinical trial found that tezepelumab, after therapeutic optimization… -to-very severe chronic obstructive pulmonary disease, the … In conclusion, up-to-date evidence confirms tezepelumab …

… reduced the annualized rate of moderate or severe COPD … COPD, tezepelumab reduced type 2 inflammatory biomarker levels over 52 weeks. A numerical improvement in tezepelumab …

Chronic obstructive pulmonary disease (COPD) is a heterogeneous pulmonary disorder characterized by persistent airflow limitation and symptoms of progressive dyspnea, cough, and sputum. While traditionally linked to type 1 immunity, a significant subset of patients presents with eosinophil-predominant type 2 inflammation. These individuals remain at risk of exacerbations despite receiving triple therapy, underscoring the need for novel biologics targeting type 2 pathways. Monoclonal antibodies against targets such as IL-5/IL-5Rα, IL-4, IL-13, IL-33/ST-2, and thymic stromal lymphopoietin (TSLP) have shown considerable promise. Therefore, the identification of accurate and accessible biomarkers for type 2 inflammation is crucial. This review summarizes the current applications and future prospects of emerging biologics in eosinophilic COPD, with a specific focus on the role of biomarkers.

… IL-33, IL-25, and TSLP are a triad of alarmins that are released by … eosinophilic inflammation both via the ILC2 and Th2 pathway. Tezepelumab, a monoclonal antibody blocking TSLP, …

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory degenerative disease. Disease exacerbations accelerate lung function deterioration. Airway epithelium has a central role in COPD pathophysiology. Airway epithelium releases alarmins including the thymic stromal lymphopoietin (TSLP) in response to exogenous stressors. Notch-1 in the nucleus acts as inhibitor of TSLP gene expression. Here, we investigated, in human bronchial epithelial cells, the effects of cigarette smoke extract (CSE) in TSLP production exploring the relationship with oxidative stress events and with Notch-1 signaling. In CSE exposed 16HBE, the effects of carbocysteine were assessed on: intracellular and extracellular oxidative stress; nuclear Notch-1 expression; TSLP gene expression. The TSLP levels in sera from non-smokers, smokers and exacerbated COPD patients (before and after therapy with carbocysteine) were also explored. CSE induced TSLP gene expression and oxidative stress and reduced nuclear expression of Notch-1 in 16HBE. The use of an electrochemical sensor allowed a reliable tool to assess oxidative stress. TSLP concentrations were higher in sera from smokers and exacerbated COPD than in sera from non-smokers. Carbocysteine was able to counteract the effects of CSE in oxidative stress and in TSLP gene expression in 16HBE and to reduce TSLP in exacerbated COPD. In conclusion, increased oxidative stress induced by smoke exposure in airway epithelium leads to increased TSLP production and carbocysteine in vitro and in vivo mitigates the induced TSLP production. Oxidative stress detection by electrochemical sensors can open new avenues for evaluating epithelial damage and for identifying patients eligible to alarmin targeted biologics.

In the respiratory system macrophages and dendritic cells collaborate as sentinels against foreign particulate antigens. The study used a triple-cell co-culture model, utilizing nasal epithelial cells, along with: monocyte derived macrophages (moMφs), and monocyte derived DCs (moDCs). Cell cultures from 15 controls, 14 asthma and 11 COPD patients were stimulated with IL-13 and poly I:C for 24 h. Co-cultivation of epithelial cells with moMφs and moDCs increased TSLP level only in asthma and the effect of IL-13 and poly I:C stimulation differed in all groups. Asthma epithelial cells expressed higher level of receptors TSLPR, ST2 and IL-17RA than controls and increased number of ST2 + ciliated and IL17RA + secretory cells. Cytokine expression in respiratory epithelium may be influenced by structural and immunological cell interaction. TSLP pathway may be associated with secretory, while IL-33 with ciliated cells. The impaired function of respiratory epithelium may impact cell-to-cell interactions in asthma.

Globally, nearly 400 million persons have COPD, and COPD is one of the leading causes of hospitalisation and mortality across the world. While it has been long-recognised that COPD is an inflammatory lung disease, dissimilar to asthma, type 2 inflammation was thought to play a minor role. However, recent studies suggest that in approximately one third of patients with COPD, type 2 inflammation may be an important driver of disease and a potential therapeutic target. Importantly, the immune cells and molecules involved in COPD-related type 2 immunity may be significantly different from those observed in severe asthma. Here, we identify the important molecules and effector immune cells involved in type 2 airway inflammation in COPD, discuss the recent therapeutic trial results of biologicals that have targeted these pathways and explore the future of therapeutic development of type 2 immune modulators in COPD. Shareable abstract Type 2 airway inflammation in COPD is different than that in severe asthma. There are several very promising therapeutic targets in this pathway to improve health outcomes of patients living with COPD. https://bit.ly/4a6se3y

Corticosteroid is the most widely used anti-inflammatory agent for asthma and chronic obstructive pulmonary disease (COPD). However, most of the severe asthmatics and COPD patients show poor response to the anti-inflammatory benefits of corticosteroids. Corticosteroid resistance is a major therapeutic challenge to the treatment of severe asthma and COPD. Cellular and molecular mechanisms underlying steroid insensitivity in severe asthma and COPD are still not fully understood. This review aims to recapitulate recent discoveries of potential contributing mechanisms of steroid resistance, and to appraise new therapeutic strategies shown to restore steroid sensitivity in experimental models of severe asthma and COPD, and in human clinical trials. It has been revealed that pro-inflammatory cytokines such as IFN-γ, TNF-α, TGF-β, IL-17A, IL-27, IL-33 and thymic stromal lymphopoietin (TSLP) may contribute to steroid resistance in severe asthma and COPD. These cytokines together with allergens, pathogens, and cigarette smoke can modulate multiple signaling pathways including PI3Kδ/Akt/mTOR, JAK1/2-STAT1/5, p38MAPK/JNK, Nrf2/HDAC2/c-Jun, heightened glucocorticoid receptor (GR)β/GRα ratio, and casein kinase 1 (CK1δ/ε)/cofilin 1, to induce steroid insensitivity. More recently, microRNAs such as miR-9, miR-21, and miR-126 have been implicated for corticosteroid insensitivity in asthma and COPD. Therapeutic strategies such as cytokine-specific biologics, signaling molecule-specific small molecule inhibitors, and microRNA-specific antagomir oligonucleotides are potentially promising approaches to reverse corticosteroid resistance. A panel of clinically effective drugs have shown promise in restoring steroid resistance in experimental models, and it is highly probable that some of these molecules can be successfully repositioned for the clinical use in COPD and severe asthma.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease that causes high rates of disability and mortality worldwide because of severe progressive and irreversible symptoms. During the period of COPD initiation and progression, the immune system triggers the activation of various immune cells, including Regulatory T cells (Tregs), dendritic cells (DCs) and Th17 cells, and also the release of many different cytokines and chemokines, such as IL-17A and TGF-β. In recent years, studies have focused on the role of IL-17A in chronic inflammation process, which was found to play a highly critical role in facilitating COPD. Specially, IL-17A and its downstream regulators are potential therapeutic targets for COPD. We mainly focused on the possibility of IL-17A signaling pathways that involved in the progression of COPD; for instance, how IL-17A promotes airway remodeling in COPD? How IL-17A facilitates neutrophil inflammation in COPD? How IL-17A induces the expression of TSLP to promote the progression of COPD? Whether the mature DCs and Tregs participate in this process and how they cooperate with IL-17A to accelerate the development of COPD? And above associated studies could benefit clinical application of therapeutic targets of the disease. Moreover, four novel efficient therapies targeting IL-17A and other molecules for COPD are also concluded, such as Bufei Yishen formula (BYF), a Traditional Chinese Medicine (TCM), and curcumin, a natural polyphenol extracted from the root of Curcuma longa.

… in diseases such as asthma and COPD. Therefore, it is essential to elucidate the action of TSLP in the signaling pathway and pathophysiology of the asthma-COPD overlap (ACO), …