Targeting CXCR1/2 suppresses TH2/TH17 cell responses and inhibits dual-pathology allergic lung inflammation.

BACKGROUND

Many chronic inflammatory diseases are driven by TH2 and TH17 immune responses and represent a major public health burden. While monoclonal antibodies against individual TH2 or TH17 cytokines or receptors show clinical benefit, their efficacy is limited by overlapping TH2/TH17 pathology. This highlights the need to identify shared upstream pathways whose inhibition could suppress both responses simultaneously.

OBJECTIVE

We sought to elucidate the role of CXCR1/2 in recruitment and proliferation of TH2 and TH17 cells during allergic airway inflammation.

METHODS

Studies used mice sensitized and challenged with cat dander extract, inducing dual TH2/TH17 lung inflammation. Expression of TH2, TH17, CXCL, and CXCR was quantified, and ex vivo CXCL stimulation of lung single-cell suspensions was used to assess TH2 and TH17 proliferation.

RESULTS

Allergen challenge upregulated Cxcl1/2/3/5 mRNA, and increased CXCR1/2+ TH2 and TH17 cells in lung single-cell suspensions. Ex vivo stimulation of these suspensions with a CXCL1/2/3/5 cocktail induced CXCR1/2-dependent proliferation of IL-4+, IL-5+, IL-13+, and IL-17+ T cells. In vivo, allergen challenge increased CXCR1/2-dependent accumulation of CXCR1+ and CXCR2+ TH2 and TH17 cells in the lungs, upregulated I l 6 and Il23 expression in granulocytes/cytokines that support TH17 responses, and exacerbated eosinophilic lung inflammation. Concurrent CXCR1 and CXCR2 blockade effectively abrogated or attenuated these effects on dual TH2/TH17 allergic inflammation.

CONCLUSIONS

CXCL chemokines play a novel role in driving proliferation of CXCR1+/CXCR2+ TH2/TH17 cells, thereby promoting overlapping TH2/TH17 lung inflammation. Targeting the CXCL-CXCR1/2 axis may provide a new strategy for treating dual TH2/TH17 diseases.