Novel Role of Macrophage Migration Inhibitory Factor in Upstream Control of the Unfolded Protein Response After Ethanol Feeding in Mice

Background Macrophage migration inhibitory factor (MIF), a pluripotent immune regulator, is an emerging mediator in alcohol‐related liver disease (ALD). MIF is associated with ALD progression through its chemokine‐ and cytokine‐like activities. Methods Mechanistic studies into the role of MIF in ethanol (EtOH)‐induced liver injury were performed in Mif−/− mice and in C57BL/6J mice treated with a small‐molecule MIF antagonist, MIF098, after Gao‐Binge (acute‐on‐chronic) EtOH feeding, an EtOH feeding protocol associated with hepatic neutrophilia and induction of the unfolded protein response (UPR). Results The MIF axis, for example, MIF and MIF receptors invariant polypeptide of major histocompatibility complex, class II antigen‐associated (CD74), CXCR2, CXCR4, and CXCR7, was enhanced in the livers of alcoholic hepatitis (AH) patients as compared to healthy controls. Mif−/− mice were protected from hepatocellular injury after Gao‐Binge feeding, independent of neutrophilia and inflammation, but were associated with the UPR. Interestingly, the UPR signature in AH patients and in mice following Gao‐Binge feeding was biased toward cell death with increased expression of pro‐cell death CCAAT–enhancer‐binding protein homologous protein (CHOP) and decreased prosurvival GRP78. The UPR and liver injury 6 hours after binge were prevented both in Mif−/− mice and in MIF098‐treated mice. However, both MIF interventions led to increased liver injury and exacerbated the hepatic UPR 9 hours after binge. Induction of upstream UPR signaling and expression of CHOP protein by thapsigargin in alpha mouse liver 12 hepatocytes were blunted by coexposure to MIF098, directly connecting MIF to UPR in hepatocytes. Conclusions The current study revealed that, in addition to its cytokine/chemokine functions, MIF is an upstream regulator of UPR in response to EtOH feeding in mice. Importantly, both MIF and UPR can either protect or contribute to liver injury, dependent upon the stage or severity of EtOH‐induced liver injury. MIF is a pivotal regulator of innate immunity in alcohol‐related liver disease and in models of ethanol feeding in mice. In the current study, MIF was discovered to control aspects of the UPR following Gao‐Binge ethanol feeding in mice independent of inflammation. Global Mif deletion (A, B) and a MIF inhibitor, MIF098 (C, D), prevented ethanol‐induced eIF2α phosphorylation and expression of CHOP protein in livers of mice. MIF098 also decreased UPR activation in thapsi