Protective role of macrophage migration inhibitory factor in nonalcoholic steatohepatitis

Abstract

MIF is an inflammatory cytokine but is hepatoprotective in models of hepatotoxin-induced liver fibrosis. Hepatic fibrosis can also develop from metabolic liver disease, such as nonalcoholic fatty liver disease (NASH). We investigated the role of MIF in high-fat or methionine- and choline-deficient diet mouse models of NASH. Mif(-/-) mice showed elevated liver triglyceride levels (WT, 53±14 mg/g liver; Mif(-/-), 103±7 mg/g liver; P<0.05) and a 2-3-fold increased expression of lipogenic genes. Increased fatty degeneration in the livers of Mif(-/-) mice was associated with increased hepatic inflammatory cells (1.6-fold increase in F4/80(+) macrophages) and proinflammatory cytokines (e.g., 2.3-fold increase in Tnf-α and 2-fold increase in Il-6 expression). However, inflammatory cells and cytokines were decreased by 50-90% in white adipose tissue (WAT) of Mif(-/-) mice. Subset analysis showed that macrophage phenotypes in livers of Mif(-/-) mice were skewed toward M2 (e.g., 1.7-fold and 2.5-fold increase in Arg1 and Il-13, respectively, and 2.5-fold decrease in iNos), whereas macrophages were generally reduced in WAT of these mice (70% reduction in mRNA expression of F4/80(+) macrophages). The protective MIF effect was scrutinized in isolated hepatocytes. MIF reversed inflammation-induced triglyceride accumulation in Hepa1-6 cells and primary hepatocytes and also attenuated oleic acid-elicited triglyceride increase in 3T3-L1 adipocytes. Protection from fatty hepatocyte degeneration was paralleled by a 2- to 3-fold reduction by MIF of hepatocyte proinflammatory cytokine production. Blockade of MIF receptor cluster of differentiation 74 (CD74) but not of CXCR2 or CXCR4 fully reverted the protective effect of MIF, comparable to AMPK inhibition. In summary, we demonstrate that MIF mediates hepatoprotection through the CD74/AMPK pathway in hepatocytes in metabolic models of liver injury.

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

“…However, our study also indicates that sCD74 inhibits the MIF/CXCR4 axis and thus induces a molecular switch from MIF‐mediated prosurvival signaling through CXCR4/AKT (profibrotic) to cell death induction by CD74 (antifibrotic). Our findings are consistent with previous studies showing that CD74 mediates antifibrotic properties whereas CXCR4 promotes profibrotic effects 26, 71…”

“…Cardioprotection by MIF is mediated through its intrinsic antioxidant capacity and by signaling through its cognate receptor CD74, a type II transmembrane glycoprotein and the surface form of class II invariant chain 25, 26, 27, 28, 29, 30, 31. In fact, The MIF/CD74/AMPK (adenosine monophosphate kinase) signaling pathway has repeatedly been demonstrated to play a pivotal protective role in acute myocardial ischemia/reperfusion injury 31, 32, 33.…”

Hepatocyte-derived macrophage migration inhibitory factor mediates alcohol-induced liver injury in mice and patients

“…Indeed, the number of both F4/80 + and Ly6C + cells in the liver were increased by ethanol in chimeric mice on a WT background, but not in mice on a Mif −/− background. This finding is consistent with published reports that indicate a role of MIF in macrophage/monocyte replenishment and recruitment during ethanol exposure[5,34]. Specifically, Barnes et al[5] found that the number of hepatic F4/80 + cells is reduced in ethanol-fed Mif −/− mice compared to WT mice, suggesting that MIF was critical for the maintenance of the hepatic macrophage population during ethanol exposure.…”

“…It is interesting to note that MIF has protective effects on hepatocytes in the face of high-fat diet-induced injury[34]. Clearly, our data suggest that this potential hepatoprotective effect of MIF is not sufficient to protect hepatocytes in the context of ethanol exposure.…”

“…Specifically, Barnes et al[5] found that the number of hepatic F4/80 + cells is reduced in ethanol-fed Mif −/− mice compared to WT mice, suggesting that MIF was critical for the maintenance of the hepatic macrophage population during ethanol exposure. Similarly, the recruitment of Ly6C + monocytes was also reduced in MIF-deficient mice after ethanol feeding and challenge with LPS[5], as well as after challenge with CCl 4 [34]. …”