Targeting CXCR1/2 suppresses T_H2/T_H17 cell responses and inhibits dual-pathology allergic lung inflammation

Many chronic inflammatory diseases are driven by T_H2 and T_H17 immune responses and represent a major public health burden. While monoclonal antibodies against individual T_H2 or T_H17 cytokines or receptors show clinical benefit, their efficacy is limited by overlapping T_H2/T_H17 pathology. This highlights the need to identify shared upstream pathways whose inhibition could suppress both responses simultaneously.

We sought to elucidate the role of CXCR1/2 in recruitment and proliferation of T_H2 and T_H17 cells during allergic airway inflammation.

Studies used mice sensitized and challenged with cat dander extract, inducing dual T_H2/T_H17 lung inflammation. Expression of T_H2, T_H17, CXCL, and CXCR was quantified, and ex vivo CXCL stimulation of lung single-cell suspensions was used to assess T_H2 and T_H17 proliferation.

Allergen challenge upregulated Cxcl1/2/3/5 mRNA, and increased CXCR1/2⁺ T_H2 and T_H17 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⁺ T_H2 and T_H17 cells in the lungs, upregulated I l 6 and Il23 expression in granulocytes/cytokines that support T_H17 responses, and exacerbated eosinophilic lung inflammation. Concurrent CXCR1 and CXCR2 blockade effectively abrogated or attenuated these effects on dual T_H2/T_H17 allergic inflammation.

CXCL chemokines play a novel role in driving proliferation of CXCR1⁺/CXCR2⁺ T_H2/T_H17 cells, thereby promoting overlapping T_H2/T_H17 lung inflammation. Targeting the CXCL-CXCR1/2 axis may provide a new strategy for treating dual T_H2/T_H17 diseases.