MERTK(+/hi) M2c Macrophages Induced by Baicalin Alleviate Non-Alcoholic Fatty Liver Disease

Junior,; Lai, Yin-Siew; Nguyen, Huyen Thi; Salmanida, Farrah P.; Chang, Ko-Tung

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. An accumulation of fat, followed by inflammation, is the major cause of NAFLD progression. During inflammation, macrophages are the most abundant immune cells recruited to the site of injury. Macrophages are classified into “proinflammatory” M1 macrophages, and “anti-inflammatory” M2 macrophages. In NAFLD, M1 macrophages are the most prominent macrophages that lead to an excessive inflammatory response. Previously, we found that baicalin could polarize macrophages into anti-inflammatory M2c subtype macrophages with an increased level of MERTK expression. Several studies have also shown a strong correlation between MERTK expression and cholesterol efflux, efferocytosis, as well as phagocytosis capability. Therefore, in this study, we aim to elucidate the potential and efficacy of mononuclear-cell (MNC)-derived MERTK(+/hi) M2c macrophages induced by baicalin as a cell-based therapy for NAFLD treatment. In our results, we have demonstrated that a MERTK(+/hi) M2c macrophage injection to NAFLD mice contributes to an increased level of serum HDL secretion in the liver, a decline in the circulating CD4(+)CD25(−) and CD8(+)CD25(−) T cells and lowers the total NAFLD pathological score by lessening the inflammation, necrosis, and fibrosis. In the liver, profibrotic COL1A1 and FN, proinflammation TNFα, as well as the regulator of lipid metabolism PPARɣ expression, were also downregulated after injection. In parallel, the transcriptomic profiles of the injected MERTK(+/hi) M2c macrophages showed that the various genes directly or indirectly involved in NAFLD progression (e.g., SERPINE1, FADS2) were also suppressed. Downregulation of cytokines and inflammation-associated genes, such as CCR5, may promote a pro-resolving milieu in the NAFLD liver. Altogether, cell-based therapy using MERTK(+/hi) M2c macrophages is promising, as it ameliorates NAFLD in mice.