M2 Kupffer cells promote M1 Kupffer cell apoptosis: A protective mechanism against alcoholic and nonalcoholic fatty liver disease

Abstract

Alcoholic and nonalcoholic fatty liver disease (ALD and NAFLD) are the predominant causes of liver-related mortality in Western countries. We have shown that limiting classical (M1) Kupffer cell (KC) polarization reduces alcohol-induced liver injury. Herein, we investigated whether favoring alternatively activated M2 KCs may protect against ALD and NAFLD. Ongoing alcohol drinkers and morbidly obese patients, with minimal hepatic injury and steatosis, displayed higher hepatic expression of M2 genes, as compared to patients with more severe liver lesions; individuals with limited liver lesions showed negligible hepatocyte apoptosis but significant macrophage apoptosis. Experiments in mouse models of ALD or NAFLD further showed that BALB/c or resveratrol-treated mice fed alcohol or a high-fat diet displayed preponderant M2 KC polarization, M1 KC apoptosis, and resistance to hepatocyte steatosis and apoptosis, as compared to control C57BL6/J mice. In vitro experiments in isolated KC, peritoneal, and Raw264.7 macrophages demonstrated that M1 macrophage apoptosis was promoted by conditioned medium from macrophages polarized into an M2 phenotype by either interleukin (IL)4, resveratrol, or adiponectin. Mechanistically, IL10 released from M2 cells promoted M1 death, and anti-IL10 antibodies blunted the proapoptic effects of M2-conditioned media. IL10 secreted by M2 KCs promoted selective M1 death by a mechanism involving activation of arginase in high inducible nitric oxide synthase-expressing M1 KCs. In alcohol-exposed mice, neutralization of IL10 impaired M1 apoptosis. Conclusion: These data uncover a novel mechanism regulating the M1/M2 balance that relies on apoptotic effects of M2 KCs towards their M1 counterparts. They suggest that promoting M2-induced M1 KC apoptosis might prove a relevant strategy to limit alcohol-and high fat-induced inflammation and hepatocyte injury. (HEPATOLOGY 2014;59:130-142)

Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis (NASH)

“…Furthermore, the addition of recombinant AnxA1 to hepatic macrophages isolated from NASH livers promotes IL-10 production and the down-modulation of M1 responses . In the same vein, Wan and co-workers (Wan et al, 2014) have shown that in mice with NAFLD IL-10 secretion induces the apoptosis of M1-activated macrophages hampering the severity of lobular inflammation.…”

“…4). To get more inside in the mechanisms leading to the decline of M1 responses we measured macrophage production of anti-inflammatory proteins such as interleukin-10 (IL-10) and annexin A1 (AnxA1) that have been previously implicated in modulating hepatic inflammation in NASH (Wan et al, 2014, Moschen et al, 2012. Flow cytometry showed that the fraction of cells producing IL-10 and AnxA1 increased among F4/80 + hepatic macrophages cells isolated from 8 weeks MCD-fed mice (Fig.…”

Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration

“…10,11 Several reports suggest that chronic inflammation, which is marked by elevated serum levels of pro-inflammatory cytokines/chemokines such as tumor necrosis factor alpha (TNF-a), IL-6, IL-8 and monocyte chemoattractant protein-1, enhances disease progression owing to the recruitment of neutrophils, monocytes and macrophages. [10][11][12][13] Although a role for Kupffer cells and neutrophils in the progression of ALD is acknowledged, 10,11,13 there is much to be understood regarding how various immune cells interact and contribute to alcohol-induced liver injury.…”

Pathogenesis of Kupffer Cells in Cholestatic Liver Injury

“…Another study using BALB/c and C57BL/6 mice has shown that M2 Kupffer cells induce M1 Kupffer cell apoptosis via IL-10 secretion and regulate M1/M2 balance, leading to protective effects against alcohol or high-fat dieteinduced hepatic steatosis and apoptosis. 36 These findings suggest that activation of M2 Kupffer cells and the regulation of M1/M2 balance could be a potential target of treatment for liver diseases.…”