Dual role for CXCR3 and CCR5 in asthmatic type 1 inflammation

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:149

Article

Gauthier, Marc¹  Kale, Sagar Laxman¹  Oriss, Timothy B.^1,2  Scholl, Kathryn¹  Das, Sudipta¹  Yuan, Huijuan¹  Hu, Sanmei¹  Chen, Jie¹  Camiolo, Matthew¹  Ray, Prabir^1,2  Wenzel, Sally^1,3  Ray, Anuradha^1,2 

[1] Univ Pittsburgh, Sch Med, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA

[2] Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA USA

[3] Univ Pittsburgh, Sch Environm & Occupat Hlth, Pittsburgh, PA USA

关键词: CXCR3;    CXCL9;    CXCL10;    CCL5;    CCR5;    IFN-gamma;    severe asthma;    maraviroc;   

DOI  :  10.1016/j.jaci.2021.05.044

来源: Elsevier

【 摘 要 】

Background: Many patients with severe asthma (SA) fail to respond to type 2 inflammation-targeted therapies. We previously identified a cohort of subjects with SA expressing type 1 inflammation manifesting with IFN-gamma expression and variable type 2 responses. Objective: We investigated the role of the chemotactic receptors C-X-C chemokine receptor 3 (CXCR3) and C-C chemokine receptor 5 (CCR5) in establishing type 1 inflammation in SA. Methods: Bronchoalveolar lavage microarray data from the Severe Asthma Research Program 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 a US Food and Drug Administration-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-gamma expression showed higher asthma severity. IFN-gamma expression was correlated with CXCR3 and CCR5 expression, but in Cxcr3(-/- )and Ccr5(-/-) mice type 1 inflammation was preserved in a murine SA model, most likely owing to compensation by the other pathway. Incorporation of maraviroc into 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. Although 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 individuals with type 1-high asthma.

【 授权许可】

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