Dual role for CXCR3 and CCR5 in asthmatic type 1 inflammation

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.