Activation of the P2RX7/IL-18 pathway in immune cells attenuates lung fibrosis.

Abstract

Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease associated with progressive and irreversible deterioration of respiratory functions that lacks curative therapies. Despite IPF being associated with a dysregulated immune response, current antifibrotics aim only at limiting fibroproliferation. Transcriptomic analyses show that theaxis is downregulated in IPF patients and that P2X7 has immunoregulatory functions. Using our positive modulator of P2X7, we show that activation of the P2X7/IL-18 axis in immune cells limits lung fibrosis progression in a mouse model by favoring an antifibrotic immune environment, with notably an enhanced IL-18-dependent IFN-γ production by lung T cells leading to a decreased production of IL-17 and TGFβ. Overall, we show the ability of the immune system to limit lung fibrosis progression by targeting the immunomodulator P2X7. Hence, treatment with a small activator of P2X7 may represent a promising strategy to help patients with lung fibrosis.