Irisin is a hormone-like myokine that regulates cell signaling pathways and exerts anti-inflammatory effects. However, the specific molecular mechanisms involved in this process are currently unknown. The present study explored the role and mechanisms underlying the functions of irisin in alleviating acute lung injury (ALI). The present study used MH-S, an established murine alveolar macrophage-derived cell line, and a mouse model of lipopolysaccharide (LPS)-induced-ALI to examine the efficacy of irisin against ALI in vitro and in vivo, respectively. Fibronectin type III repeat-containing protein/irisin was expressed in the inflamed lung tissue, but not in normal lung tissue. Exogenous irisin reduced alveolar inflammatory cell infiltration and pro-inflammatory factor secretion in mice following LPS stimulation. It also inhibited the polarization of M1-type macrophages and promoted the repolarization of M2-type macrophages, thus reducing the LPS-induced production and secretion of interleukin (IL)-1β, IL-18 and tumor necrosis factor-α. In addition, irisin reduced the release of the molecular chaperone heat shock protein 90 (HSP90), inhibited the formation of nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3) inflammasome complexes, and decreased the expression of caspase-1 and the cleavage of gasdermin D (GSDMD), leading to reduced pyroptosis and the accompanying inflammation. On the whole, the findings of the present study demonstrate that irisin attenuates ALI by inhibiting the HSP90/NLRP3/caspase-1/GSDMD signaling pathway, reversing macrophage polarization and reducing the pyroptosis of macrophages. These findings provide a theoretical basis for understanding the role of irisin in the treatment of ALI and acute respiratory distress syndrome.

Background: PM2.5 exposure is one of the major inducements of various respiratory diseases and related mortality. Meanwhile, irisin, a metabolism and thermogenesis-related hormone, is found to be protective against acute lung injury induced by LPS, which indicates its therapeutic function in lung injury. However, the function and underlying mechanism of irisin in PM2.5-induced acute lung injury (ALI) are still unclear. This study is aimed to discover the potential mechanisms of irisin in PM2.5-induced acute lung injury. Methods: Atg5 deficient mice and cells were established to clarify the relationship between irisin and autophagy in PM2.5-induced ALI. We also used Ad-mCherry-GFP-LC3B as a monitor of autophagy flux to claim the effects of irisin on autophagy. Western blotting and qPCR were used to reveal the molecular mechanism. Results: As a result, PM2.5 exposure induced lung injury whereas mitigated by irisin. Moreover, PM2.5 hampered autophagy flux, characterized by accumulation of p62, and autophagosomes, as well as blocked autolysosomes. Irisin improved the disturbed autophagy flux, which was abrogated by deficiency of Atg5. Additionally, we demonstrated that irisin activated AMPK and inhibited mTOR, which indicated the enhanced autophagy. Moreover, blockage of AMPK by compound C terminated irisin's induction of autophagy in cultured MH-S cells. Conclusion: Our findings reveal that irisin performs protective effects against PM2.5-induced ALI by activating autophagy through AMPK/mTOR signaling pathway.

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