These data do not argue for a contribution of T cells in M1 apoptosis. We examined the relationship of hepatic M2 signature to the severity of steatosis in liver biopsies obtained from morbidly obese patients undergoing bariatric surgery (Table 1). Patients were classified into two groups, with minimal (S0) and elevated (S2) selleck screening library steatosis. S0 patients showed a higher mRNA expression of the M2 markers CD206 and CD163 as compared to S2 patients (Fig. 7D), whereas the expression of IL10 and that of the M1 marker

TNF-α was similar in both groups (not shown). Cleaved-caspase-3/CD68 positive macrophages were detected in liver biopsy of S0 and S2 patients but was more frequent in S0 patients, who showed negligible hepatocyte apoptosis (Fig. 7E). Activation of Kupffer cells to secrete proinflammatory mediators is a key event in the initiation of fatty liver disease, and limiting their polarization into an M1 phenotype is considered an attractive strategy.[12, 26] In the present study, combining human data, animal models, and cell culture experiments, we identify

a novel mechanism neutralizing M1 Kupffer cell emergence, which relies on selective induction of their apoptosis by selleck M2 Kupffer cells. The successful resolution of inflammatory processes requires the inhibition of proinflammatory signaling. M2 macrophages typically fulfill this function, owing to their high capacity to counteract the proinflammatory functions of classical macrophages (M1).[1, 2] We postulated that favoring M2 KC polarization might protect against fatty liver disease. The relevance of this hypothesis was evaluated in liver biopsies from either ongoing alcohol abusers or morbidly obese patients, with mild forms of ALD or NAFLD, and classified according to the degree of liver lesions. Individuals with limited liver lesions displayed higher hepatic M2 gene expression

Janus kinase (JAK) and negligible hepatocyte apoptosis, as compared to patients with more severe lesions. These data provided a link between M2 KC polarization and the prevention of fatty liver disease against progression to more severe forms of injury. Moreover, they raise the intriguing possibility that differences in Kupffer cell phenotype might account for the variability in susceptibility of individuals to ALD or NAFLD, in addition to incriminated environmental, genetic, and metabolic factors.[27, 28] We also investigated the relationship between M2 KC polarization, prevention, or regression of fatty liver injury in mice models. Genetic or pharmacological interventions favoring preponderant M2 KC polarization (i.e., BALB/c mice fed alcohol, and resveratrol-treated C57BL6/J mice fed either alcohol or high fat) were associated with impaired M1 response and limited liver injury.