Role of AKAP12 in recovery from intestinal inflammation

Abstract

Macrophages exhibit phenotypic plasticity, as they have the ability to switch their functional phenotypes during inflammation and recovery. Simultaneously, the mechanical environment is actively changing. However, how these dynamic alteration affect the macrophage phenotype is unknown. Here, I show that the extracellular matrix (ECM) constructed by AKAP12+ colon mesenchymal cells (CMCs) generates M2 macrophages by regulating their shape during recovery. Notably, round macrophages were present in the linear and loose ECM of inflamed colons and polarized to the M1 phenotype. In contrast, ramified macrophages emerged in the contracted ECM of recovering colons and mainly expressed M2 macrophage markers. These contracted structures were not observed in the inflamed colons of AKAP12 knockout (KO) mice. Consequently, the proportion of M2 macrophages in inflamed colons was lower in AKAP12 KO mice than in WT mice. In addition, clinical symptoms and histological damage were more severe in AKAP12 KO mice than in WT mice. In experimentally remodelled collagen gels, WT CMCs drove the formation of a more compacted structure than AKAP12 KO CMCs, which promoted the polarization of macrophages toward an M2 phenotype. These results demonstrate that tissue contraction during recovery provides macrophages with the physical cues that drive M2 polarization.