[5] Inflammation driven by M1 macrophages is counterbalanced by alternatively polarized M2 macrophages that promote resolution of inflammation and tissue repair.[1, 2] Beneficial properties of alternative M2 macrophages are reported in several inflammatory disorders, including insulin resistance,[6, 7] atherosclerosis,[3] muscle repair,[8] infectious colitis,[4] and chronic glomerulopathies.[9] Altogether, dysregulation of the M1/M2

phenotypic balance is emerging as a central mechanism TGF-beta inhibitor governing the pathogenesis of chronic inflammatory diseases, suggesting that strategies restraining M1 macrophage polarization and/or favoring the M2 macrophage phenotype may protect against exacerbated inflammation and thus limit tissue injury. Alcoholic and nonalcoholic fatty liver disease Talazoparib cost (ALD and NAFLD) are leading causes of liver-related morbidity and mortality in Western countries.[10, 11] Clinical findings and experimental data have demonstrated that activation of Kupffer cells

(KCs) is a central event in the initiation of liver injury.[11-14] The resulting exacerbated release of M1 Kupffer cell-derived mediators contributes to the pathogenesis of several liver lesions, namely, hepatocyte steatosis and apoptosis, inflammatory cell recruitment, and activation of fibrogenesis.[14-17] We have previously shown that limiting M1 KC polarization reduces ALD progression.[6, 7, 14] Here we investigated the impact of M2 KC polarization on alcohol- and high fat-induced liver injury and uncover a novel mechanism limiting M1 KC function, which relies on a proapoptotic effect of M2 KCs for their M1 counterparts. All subjects gave their informed written consent to participate in this research study according to French legislation regarding Ethic and Human Research (Huriet-Serusclat law, the “Comité Consultatif de Protection des Personnes dans la Recherche Biomedicale de Nice” approved this study, Nos. 03.613 and 03.017). The M2 signature was investigated in liver biopsies from 15 heavy alcohol drinkers with similar age and daily this website alcohol intakes, and limited fibrosis, as defined by a fibrosis stage

<2 according to the modified METAVIR scoring system (Table 1). Patients were part of a previously characterized cohort of 109 consecutive alcohol drinkers.[18] Patients were divided into two groups according to serum transaminase levels: group 1 with minimally increased transaminases (10 patients with aspartate aminotransferase [AST], < 2 ULN [(upper limit of normal] and normal alanine aminotransferase [ALT]), and group 2 with elevated transaminases (five patients with AST >2× ULN and ALT >ULN). All patients had ongoing alcohol intoxication until admission. Ultrasound-guided liver biopsy was performed after a mean period of 4 ± 1.9 days of alcohol abstinence, with no difference in duration of abstinence between groups (group 1; 4.5 ± 1.