Impaired CCR9/CCL25 signalling induced by inefficient dendritic cells contributes to intestinal immune imbalance in nonalcoholic steatohepatitis

Abnormal crosstalk between gut immune and the liver was involved in nonalcoholic steatohepatitis (NASH). Mice with methionine choline-deficient (MCD) diet-induced NASH presented an imbalance of pro-(IL-6 and IFN-γ) and anti-inflammatory cytokines (IL-10) in the intestine. We also clarified that the ratio of CD4⁺ T cells and found that the NASH mesenteric lymph node (MLN) presents decreased numbers of CD4⁺Th17 cells but increased numbers of CD4⁺CD8⁺FoxP3⁺ regulatory T cells (Tregs). Furthermore, the intestinal immune imbalance in NASH was attributed to impaired gut chemokine receptor 9 (CCR9)/chemokine ligand 25 (CCL25) signalling, which is a crucial pathway for immune cell homing in the gut. We also demonstrated that CD4⁺CCR9⁺ T cell homing was dependent on CCL25 and that the numbers and migration abilities of CD4⁺CCR9⁺ T cells were reduced in NASH. Interestingly, the analysis of dendritic cell (DC) subsets showed that the numbers and retinal dehydrogenase (RALDH) activity of CD103⁺CD11b⁺ DCs were decreased and that the ability of these cells to upregulate CD4⁺ T cell CCR9 expression was damaged in NASH. Taken together, impaired intestinal CCR9/CCL25 signalling induced by CD103⁺CD11b⁺ DC dysfunction contributes to the gut immune imbalance observed in NASH.

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