MCP-induced protein 1 attenuates sepsis-induced acute lung injury by modulating macrophage polarization via the JNK/c-Myc pathway.

Sepsis is a potentially fatal systemic inflammatory response syndrome caused by infection. In this study, we evaluated the effects of MCP-induced protein 1 (MCPIP1), a recently discovered inflammation-related ribonuclease, on sepsis-induced acute lung injury (ALI) and investigated the underlying mechanisms. Cecal ligation puncture and lipopolysaccharide induction were performed on Sprague-Dawley rats and RAW264.7 cells, respectively, to establish sepsis-induced ALI models. The proteasome inhibitor MG132 used as an activator of MCPIP1 overexpression, and we showed that MG132 can indeed increase the expression of MCPIP1. MCPIP1 overexpression induced by MG132 alleviated sepsis-induced pathologic changes, water content and protein leakage in the lungs, and induction of systemic inflammatory mediators, and improved the 7-day mortality rate in the model rats. We also showed that MCPIP1 p showed romoted macrophage polarization from the M1 to the M2 type in sepsis-induced ALI. Furthermore, MCPIP1-enhanced M2 polarization was inhibited by an MCPIP1-targeting small interfering RNA (siMCPIP1) in RAW264.7 cells. Further mechanistic studies showed that the promotive effect of MCPIP1 on M2 polarization was related to the inhibition of c-Jun N-terminal kinase (JNK) and its downstream transcription factor c-Myc in the in vitro model. Conversely, siMCPIP1 transfection resulted in the recovery of JNK and c-Myc expression in LPS-treated cells. Taken together, these findings indicate that MCPIP1 plays a protective role in sepsis-induced ALI by modulating macrophage polarization through inhibition of the JNK/c-Myc signaling pathway. Our study presents a potentially novel therapeutic strategy for the treatment of lung injury involving the inflammatory cascade.