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The C-type lectin receptor Mincle is known for its important role in innate immune cells in recognizing pathogen and damage associated molecular patterns. Here we report a T cell–intrinsic role for Mincle in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). Genomic deletion of Mincle in T cells impairs TH17, but not TH1 cell-mediated EAE, in alignment with significantly higher expression of Mincle in TH17 cells than in TH1 cells. Mechanistically, dying cells release β-glucosylceramide during inflammation, which serves as natural ligand for Mincle. Ligand engagement induces activation of the ASC-NLRP3 inflammasome, which leads to Caspase8-dependent IL-1β production and consequentially TH17 cell proliferation via an autocrine regulatory loop. Chemical inhibition of β-glucosylceramide synthesis greatly reduces inflammatory CD4+ T cells in the central nervous system and inhibits EAE progression in mice. Taken together, this study indicates that sensing of danger signals by Mincle on TH17 cells plays a critical role in promoting CNS inflammation.

Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the two major types of chronic liver disease worldwide. Inflammatory processes play key roles in the pathogeneses of fatty liver diseases, and continuous inflammation promotes the progression of alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). Although both ALD and NAFLD are closely related to inflammation, their respective developmental mechanisms differ to some extent. Here, we review the roles of multiple immunological mechanisms and therapeutic targets related to the inflammation associated with fatty liver diseases and the differences in the progression of ASH and NASH. Multiple cell types in the liver, including macrophages, neutrophils, other immune cell types and hepatocytes, are involved in fatty liver disease inflammation. In addition, microRNAs (miRNAs), extracellular vesicles (EVs), and complement also contribute to the inflammatory process, as does intertissue crosstalk between the liver and the intestine, adipose tissue, and the nervous system. We point out that inflammation also plays important roles in promoting liver repair and controlling bacterial infections. Understanding the complex regulatory process of disrupted homeostasis during the development of fatty liver diseases may lead to the development of improved targeted therapeutic intervention strategies.

Hepatic fibrosis is a dynamic process resulting from excessive deposition of extracellular matrix in the liver; uncontrolled progression of fibrosis can eventually lead to liver cirrhosis and/or hepatocellular carcinoma. The fibrogenic process is complex and modulated by a number of both hepatic and extra-hepatic biological factors. Growing evidence indicates that adipokines, a group of cytokines produced by adipose tissue, impart dynamic functions in liver and are involved in modulation of hepatic fibrosis. In particular, two key adipokines, adiponectin and leptin, directly regulate many biological responses closely associated with development and progression of hepatic fibrosis. Leptin acts as a pro-fibrogenic cytokine, while adiponectin possesses anti-fibrogenic and anti-inflammatory properties. Adiponectin, acting via its cognate receptors, adiponectin receptors 1 and 2, potently suppresses fibrosis and inflammation in liver via multiple mechanisms. This review summarizes recent findings concerning the role of adiponectin in fibrogenic process in liver and addresses the underlying molecular mechanisms in modulation of fibrosis.

Background C5a and its cognate receptor, C5a receptor (C5aR), key elements of complement, are critical modulators of liver immunity and fibrosis. However, the molecular mechanism for the cross talk between complement and liver fibrosis is not well understood. C5a is a potent chemokine regulating migration of cells in the innate immune system. Since activation and migration of hepatic stellate cells (HSC) are hallmarks of liver fibrosis, we hypothesized that C5a contributes to fibrosis by regulating HSC activation and/or migration. Results Primary cultures of mouse HSC increased expression of alpha smooth muscle actin (α-SMA) and collagen 1A (Col1A1) mRNA in response to activation on plastic. Expression of mRNA for C5aR, but not C5L2, a second C5a receptor that acts as a negative regulator, increased in parallel with markers of HSC activation in culture. Increased expression of C5aR on activated HSC was confirmed by immunocytochemistry. Cell surface expression of C5aR was also detected by flow cytometry on activated HSC isolated from mice expressing GFP under the control of the collagen promoter after exposure to chronic carbon tetrachloride. To understand the functional significance of C5aR expression in HSC, we next investigated whether C5a influenced HSC activation and/or migration. Challenge of HSC with C5a during culture had no effect on expression of α-SMA and Col1A1, suggesting that C5a did not influence HSC activation. Another important characteristic of HSC is their migratory capacity; migration of HSC in response to platelet derived growth factor (PDGF) and monocyte chemoattractant protein-1 (MCP-1) has been well characterized. Challenge of HSC with C5a enhanced HSC migration almost as efficiently as PDGF in a two-dimensional wound healing and Boyden chamber migration assays. C5a also stimulated expression of MCP-1. C5a-induced cell migration was slowed, but not completely inhibited, in presence of 227016, a MCP-1 receptor antagonist, suggesting C5a-induced migration occurs via both MCP-1-dependent and -independent mechanisms. Conclusions These data reveal that C5a regulates migration of HSC and suggest a novel mechanism by which complement contributes to hepatic fibrosis. C5a and its receptors are therefore potential therapeutic targets for the prevention and/or treatment of liver fibrosis.

Alcoholic liver disease (ALD) develops in approximately 20% of all alcoholics with a higher prevalence in females [1]. The development of fibrosis and cirrhosis is a complex process involving both parenchymal and non-parenchymal cells resident in the liver, as well as the recruitment of additional cell types to the liver in response to damage and inflammation [2]. Kupffer cells, the resident macrophages in the liver, are critical to the onset of ethanol-induced liver injury. Ablation of Kupffer cells prevents the development of fatty liver and inflammation, early events in the progression of ethanol-induced liver damage, in rats chronically exposed to ethanol via intragastric feeding [3]. Endotoxin (or lipopolysaccharide (LPS)), a component of the cell wall of gram-negative bacteria, is an important activator of Kupffer cells, stimulating the production of inflammatory and fibrogenic cytokines, as well as reactive oxygen species. LPS concentration is increased in the blood of alcoholics [4,5] and rats exposed to ethanol via intra-gastric infusion [6], probably due to impaired barrier function of the intestinal mucosa [7]). In a series of elegant experiments using transgenic animals from the laboratory of Ron Thurman, a working model for the development of alcoholic liver disease has been developed. This model proposes that increased exposure of Kupffer cells to LPS during chronic ethanol consumption results in increased production of inflammatory mediators, in particular TNF-alpha and reactive oxygen species, leading to the progression of fatty liver, inflammation and fibrosis, characteristic of ALD [7]. In addition to this increased exposure of Kupffer cells to LPS in response to ethanol, we and others have shown that chronic ethanol also sensitizes Kupffer cell responses to LPS [8,9]. We hypothesize that increased sensitivity to LPS stimulation after chronic ethanol exposure likely contributes to the progression of liver injury. Role of TNF-alpha in the progression of alcoholic liver disease TNF-alpha is thought to play a particularly critical role in the pathogenesis of ALD. TNF-alpha is one of the principal mediators of the inflammatory response in mammals, transducing differential signals that regulate cellular activation and proliferation, cytotoxicity and apoptosis [10,11] In addition to its role in acute septic shock, TNF-alpha has been implicated in the pathogenesis of a wide variety of inflammatory diseases [11,12,14] as well as in the progression of alcoholic liver disease [7,15] The role of TNF-alpha in the development of ethanol-induced liver injury has been well characterized in animal models [7,15] Production of TNF-alpha is one of the earliest responses of the liver to injury [15]. Circulating TNF-alpha is increased in the blood of alcoholics and in animals chronically exposed to ethanol [16,17]. Antibiotic treatment decreases TNF-alpha expression and ethanol-induced liver injury in rats exposed to ethanol via intra-gastric infusion [7], suggesting that increased TNF-alpha after ethanol exposure is due, at least in part, to increased exposure to LPS. In addition to increasing LPS exposure, chronic ethanol also increases sensitivity to LPS. For example, long-term ethanol consumption increases the susceptibility of rats to endotoxin-induced liver injury [8,18]. Moreover, we have shown that LPS-stimulated TNF-alpha secretion is increased in Kupffer cells isolated from rats fed ethanol in their diet for 4 weeks compared to pair-fed controls [9,19,20].