MAPKAP Kinase-2 signaling enhances the resolution of colonic inflammation through specialized pro-resolving mediators

Abstract

Failure to resolve acute inflammation contributes to chronic inflammatory diseases, including inflammatory bowel disease, and inflammation associated cancer. MAPKAP kinase-2 (MK2), a stress-activated effector of p38MAPK, is best known for promoting onset and amplification of inflammation through post-transcriptional regulation of cytokines. Here we identify an unexpected role for MK2 in coordinating resolution of intestinal inflammation. Following dextran sodium sulfate induced colonic injury, MK2 deficient mice developed more severe, persistent inflammation, with sustained proinflammatory cytokine and chemokine production, prolonged neutrophil accumulation, and impaired macrophage recruitment during recovery. Myeloid-restricted MK2 deficiency recapitulated the impaired resolution phenotype. Lipid mediator metabololipidomics revealed MK2 deficient colons failed to undergo the transition from pro-inflammatory to pro-resolving lipid mediator production, exhibiting markedly reduced levels of specialized pro-resolving mediators (SPMs), including resolvins and lipoxins. Exogenous SPM administration during the recovery phase restored inflammation resolution in MK2 deficient mice, improving weight, disease activity, and mucosal healing. These findings establish a previously unrecognized role for MK2 in coordinating the transition from inflammatory injury to resolution and repair. Together with our prior finding that myeloid MK2 deficiency reduces colitis-associated tumor progression, these results suggest that inflammation associated tumorigenesis depends not simply on inflammatory injury, but on its coupling to the resolution and tissue repair that follows.