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MAPK-activated protein kinase 2 (MK2) plays a critical role in the development of inflammation. However, the modulatory mechanisms in macrophage activation and acute lung injury (ALI) have not been completely defined. Here, we reported that MK2-deficient mice (MK2 −/− ) protected against sepsis-induced ALI. In response to lipopolysaccharide (LPS) challenge, MK2 −/−  mice and myeloid cell-specific MK2 conditional knockout mice (MK2 Lyz2-KO ) exhibited attenuated inflammatory response, especially producing fewer amounts of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and macrophage inflammatory protein 2 (MIP-2). LPS treatment in vitro resulted in reduced cytokine expression in MK2 −/−  bone marrow-derived macrophages (BMDMs). Furthermore, we found that LPS-induced microRNA lethal-7e ( let-7e) expression was significantly increased in MK2 −/−  macrophages. Transfection of let-7e antagomirs into MK2 −/−  BMDM rescued LPS-induced expression of TNF-α, IL-6, and MIP-2. In contrast, transfection of let-7e mimics into MK2 +/+ BMDM decreased cytokine expression. Meanwhile, LPS-induced phosphorylation of cAMP response element-binding (CREB) protein, a substrate of MK2, was downregulated in MK2 −/−  BMDMs. Lin28, an inhibitory molecule of let-7, was significantly reduced in MK2 −/−  macrophages. Our results suggested that MK2 boosts LPS-induced macrophage activation and ALI via increasing activation of CREB and consequently, the expression of Lin28 and downregulation of let-7e.

MK2 mediates macrophage activation and acute lung injury by regulating let-7e miRNA