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Interleukin-6: A Phenotype-Agnostic Therapeutic Target for Mucus Plugs in Type 2 and Non-type 2 Asthma

ABSTRACT: Airway mucus plugs are prevalent in both type 2 (T2) and non-T2 asthma phenotypes, contributing to treatment resistance. Current biologics predominantly target T2 pathways. In our cross-sectional study of 321 patients with asthma, chest CT showed mucus plugs were prevalent in both T2 and non-T2 asthma (33.2% vs 20%, P = 0.034) and across all severities (mild-to-moderate: 27.0%; severe: 60.7%; P = 0.001). Patients with mucus plugs had higher rates of severe asthma (17.7% vs 4.9%, P < 0.001) and elevated serum and sputum IL-6 (P = 0.004; P < 0.001). Multivariable regression identified sputum IL-6 as an independent risk factor for mucus plugs (OR 4.84; 95%CI, 1.63–24.5; P = 0.020). In vivo and in vitro studies demonstrated that anti-IL-6/IL-6R treatment significantly reduced periodic acid-Schiff scores (2.80 ± 0.84 vs 4.60 ± 0.55, P = 0.004) and mucin 5 subtype AC/B expression via the PI3K mTOR signaling pathway. We further observed that 2 of 3 patients with mucus plugs exhibited significant resolution following tocilizumab treatment. These findings indicate that mucus plugs are a common feature across asthma inflammatory phenotypes and are associated with increased disease severity. IL-6 pathway inhibition offers a phenotype agnostic therapeutic strategy for mucus plug resolution in asthma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE320578 | GEO | 2026/03/03

REPOSITORIES: GEO

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Project description:Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) with asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthma is unclear. Objective: To explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthma. Methods: Primary human bronchial epithelial cell (HBEC) air-liquid interface (ALI) cultures were stimulated with IL-6 and sIL-6R to establish an IL-6TS gene signature. Two separate RNA sequencing (RNA-seq) studies were performed: The “IL-6 vs T2 study” compared gene expression after stimulation with control medium, IL-6, IL-6/sIL-6R and IL-4/IL-13, while the “JAK1-inhibition study” addressed the effect of JAK1 inhibition on IL-6TS induced gene expression. The IL-6TS gene signature was used to stratify lung epithelial transcriptomic data obtained from asthmatics (n=103) in the U-BIOPRED cohorts by hierarchical clustering. Molecular phenotyping was based on the transcriptional profiling of epithelial brushings, pathway analysis and immunohistochemistry analysis of bronchial biopsies. Results: Activation of IL-6TS in HBEC ALI cultures reduced epithelial barrier function and induced a specific epithelial gene signature enriched in airway remodeling genes. The IL-6TS signature identified a subset (n=17) of IL-6TS High asthma patients with increased epithelial expression of IL-6TS inducible genes in absence of increased systemic levels of IL-6 and sIL-6R. The IL-6TS High subset had an increased exacerbation frequency (p=0.028), blood (>300/μl; p=0.0028) and sputum (>20%; p=0.007) eosinophilia, and submucosal infiltration of CD4 T cells, CD8 T cells (p<0.001) and macrophages (p=0.001). In bronchial brushings, TLR pathway genes were up-regulated while the expression of epithelial tight junction genes was reduced (all with q<0.05). Sputum sIL-6R levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, MMP3, IL-8 and IL-1β (all with q<0.001). Conclusions: Local lung epithelial IL-6TS activation in absence of type 2 airway inflammation defines a novel subset of asthmatics and may drive airway inflammation and epithelial dysfunction in these patients.

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Interleukin-6: A Phenotype-Agnostic Therapeutic Target for Mucus Plugs in Type 2 and Non-type 2 Asthma

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