IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis.

Background: Idiopathic pulmonary fibrosis is a devastating as yet untreatable disease. We demonstrated recently the predominant role of the NLRP3 inflammasome activation and IL-1 b expression in the establishment of pulmonary inflammation and fibrosis in mice.[br/] Methods: The contribution of IL-23 or IL-17 in pulmonary inflammation and fibrosis was assessed using the bleomycin model in deficient mice.[br/] Results: We show that bleomycin or IL-1 b -induced lung injury leads to increased expression of early IL-23p19, and IL-17A or IL-17F expression. Early IL-23p19 and IL-17A, but not IL-17F, and IL-17RA signaling are required for inflammatory response to BLM as shown with gene deficient mice or mice treated with neutralizing antibodies. Using FACS analysis, we show a very early IL-17A and IL-17F expression by ROR c t + cd T cells and to a lesser extent by CD4 ab + T cells, but not by iNKT cells, 24 hrs after BLM administration. Moreover, IL-23p19 and IL-17A expressions or IL-17RA signaling are necessary to pulmonary TGF- b 1 production, collagen deposition and evolution to fibrosis.[br/] Conclusions: Our findings demonstrate the existence of an early IL-1 b -IL-23-IL-17A axis leading to pulmonary inflammation and fibrosis and identify innate IL-23 and IL-17A as interesting drug targets for IL-1 b driven lung pathology