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Dual role for CXCR3 and CCR5 in asthmatic type 1 inflammation
- Source :
- J Allergy Clin Immunol
- Publication Year :
- 2022
- Publisher :
- Elsevier BV, 2022.
-
Abstract
- BACKGROUND: Many severe asthma (SA) patients fail to respond to Type 2 inflammation targeted therapies. We previously identified a cohort of SA subjects expressing Type 1 inflammation manifesting with IFN-γ expression with variable Type 2 responses. OBJECTIVE: We investigated the role of the chemotactic receptors CXCR3 and CCR5 in establishing Type 1 inflammation in SA. METHODS: Bronchoalveolar lavage microarray data from the Severe Asthma Research Program (SARP I/II) were analyzed for pathway expression and paired with clinical parameters. Wild Type, Cxcr3(−/−) and Ccr5(−/−) mice were exposed to a Type 1(High) SA model with analysis of whole lung gene expression and histology. Wild type and Cxcr3(−/−) mice were treated with an FDA-approved CCR5 inhibitor (maraviroc) with assessment of airway resistance, inflammatory cell recruitment by flow cytometry, whole lung gene expression and histology. RESULTS: A cohort of subjects with increased IFN-γ expression showed higher asthma severity. IFN-γ expression correlated with CXCR3 and CCR5 expression but in Cxcr3(−/−) and Ccr5(−/−) mice Type 1 inflammation was preserved in a murine SA model, most likely due to compensation by the other pathway. Incorporation of maraviroc in the experimental model blunted airway hyperreactivity, despite only mild effects on lung inflammation. CONCLUSIONS: IFNG expression in asthmatic airways was strongly correlated with expression of both the chemokine receptors CXCR3 and CCR5. While these pathways provide redundancy for establishing Type 1 lung inflammation, inhibition of the CCL5/CCR5 pathway with maraviroc provided unique benefits in reducing airway hyperreactivity. Targeting this pathway may be a novel approach for improving lung function in Type 1(high) asthmatic individuals. CLINICAL IMPLICATIONS: In Type 1 high asthma, CCR5 and CXCR3 provide redundant pathways for lung inflammation, but CCR5 inhibition provides a potential novel target for reducing airway hyperreactivity.
- Subjects :
- Adult
Male
Receptors, CXCR3
Receptors, CCR5
Immunology
Bronchi
Respiratory Mucosa
CCR5 receptor antagonist
CXCR3
Severity of Illness Index
Article
CCL5
Maraviroc
Interferon-gamma
Young Adult
Chemokine receptor
chemistry.chemical_compound
medicine
Animals
Humans
Immunology and Allergy
CXCL10
Inflammation
Mice, Knockout
medicine.diagnostic_test
business.industry
Airway Resistance
Middle Aged
Asthma
respiratory tract diseases
Mice, Inbred C57BL
Bronchoalveolar lavage
chemistry
CCR5 Receptor Antagonists
CXCL9
Female
business
Bronchoalveolar Lavage Fluid
Subjects
Details
- ISSN :
- 00916749
- Volume :
- 149
- Database :
- OpenAIRE
- Journal :
- Journal of Allergy and Clinical Immunology
- Accession number :
- edsair.doi.dedup.....7ee8d61c7b589925763c7167d8ae128d