Abnormally differentiated subsets of intestinal macrophage play a key role in Th1-dominant chronic colitis through excess production of IL-12 and IL-23 in response to bacteria

Disorders in enteric bacteria recognition by intestinal macrophages (M phi) are strongly correlated with the pathogenesis of chronic colitis; however the precise mechanisms remain unclear. The aim of the current study was to elucidate the roles of M phi in intestinal inflammation by using an IL-10-deficient (IL-10(-/-)) mouse colitis model. GM-CSF-induced bone marrow-derived M phi (GM-M phi) and M-CSF-induced bone marrow-derived M phi (M-M phi) were generated from bone marrow CD11b(+) cells. M-M phi from IL-10(-/-) mice produced abnormally large amounts of IL-12 and IL-23 upon stimulation with heat-killed whole bacteria Ags, whereas M-M phi from wild-type (WT) mice produced large amounts of IL-10 but not IL-12 or IL-23. In contrast, IL-12 production by GM-M phi was not significantly different between WT and IL-10(-/-) mice. In ex vivo experiments, cytokine production ability of colonic lamina propria M phi (CLPM phi) but not splenic M phi from WT mice was similar to that of M-M phi, and CLPM phi but not splenic M phi from IL-10(-/-) mice also showed abnormal IL-12p70 hyperproduction upon stimulation with bacteria. Surprisingly, the abnormal IL-12p70 hyperproduction from M-M phi from IL-10(-/-) mice was improved by IL-10 supplementation during the differentiation process. These results suggest that CLPM phi and M-M phi act as anti-inflammatory M phi and suppress excess inflammation induced by bacteria in WT mice. In IL-10(-/-) mice, however, such M phi subsets differentiated into an abnormal phenotype under an IL-10-deficient environment, and bacteria recognition by abnormally differentiated subsets of intestinal M phi may lead to Th1-dominant colitis via IL-12 and IL-23 hyperproduction. Our data provide new insights into the intestinal M phi to gut flora relationship in the development of colitis in IL-10(-/-) mice.