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

Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease associated with progressive and irreversible deterioration of respiratory functions that lacks curative therapies. It is characterized by destruction of lung architecture due to accumulation of fibroblasts and extracellular matrix proteins, that are the main targets of current antifibrotic therapies. IPF is also associated with a dysregulated immune response, which its importance in IPF is still under debate. P2RX7 is an immunomodulator shown to favor IFN-γ production by immune cells, which is described to be antifibrotic. P2RX7 is expressed and active in IPF and we sought here to determine the ability of P2RX7 in limiting the progression of pulmonary fibrosis. We show that the P2RX7/IL-18/IFNG axis is downregulated in IPF patients. Activation of the P2RX7/NLRP3/IL-18 axis in immune cells limits lung fibrosis progression in a mouse model by favoring an anti-fibrotic immune environment, with notably enhanced IFN-γ production by lung T cells. Overall, we show the ability of the immune system to limit lung fibrosis progression by targeting the immunomodulator P2RX7. We also highlight the importance of IL-18 as a key regulator of pulmonary fibrosis and propose that high levels of active IL-18 may represent a better prognosis for IPF patients.