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

Abstract

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 À/À 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 À/À 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 À/À 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.

A selective small-molecule inhibitor of macrophage migration inhibitory factor-2 (MIF-2), a MIF cytokine superfamily member, inhibits MIF-2 biological activity

“…In the case of MIF-1, the fortuitous apposition of structural features shared by nonphysiologic enzymatic activity with those required for CD74 interaction (43) has prompted multiple efforts to identify tautomerase inhibitors that also block receptor activation (29,31,32). Several compounds have shown auspicious activity in preclinical models, including ISO-1 (27,44), MIF098 (45)(46)(47), and others (32,34,48). One small-molecule MIF antagonist that has advanced into clinical development is ibudilast, which was originally developed as a phosphodiesterase inhibitor but was discovered to inhibit MIF allosterically (49).…”

“…In 2010, the benzoxazol-2-one class of MIF-1 antagonists was reported, with MIF098 showing an IC 50 of 0.010 M (41). This orally bioavailable small-molecule inhibitor was further reported to block MIF-1 binding to the extracellular domain of CD74 to attenuate recruitment of the CD74 signaling coreceptor CD44, reduce downstream ERK1/2 phosphorylation (46), and inhibit MIF-dependent lung injury (45) and liver disease (47). The small-molecule 4-IPP, which acts a suicide substrate to covalently modify Pro-1 and inhibit MIF-1, has been reported recently to also react with Pro-1 of MIF-2 to inhibit MIF-2 tautomerization and biological activity (28).…”

Immunological mechanisms and therapeutic targets of fatty liver diseases

“…Preclinical studies with CVC, a dual inhibitor of CCR2 and CCR5, have shown promising results, 82 and MIF098, an inhibitor of the pluripotent cytokine/chemokine MIF, is also a promising agent for reducing chronic ethanol-induced liver injury in mice. 52,158 As alternatives to strategies that directly break the cycle of proinflammatory cytokine and chemokine signaling, strategies that promote anti-inflammatory responses and hepatocyte regeneration are also of interest. The most well studied are strategies involving IL22, 156,159 which has been shown to be promising from the perspectives of safety and efficacy.…”

“…Preclinical studies with CVC, a dual inhibitor of CCR2 and CCR5, have shown promising results, 82 and MIF098, an inhibitor of the pluripotent cytokine/chemokine MIF, is also a promising agent for reducing chronic ethanol-induced liver injury in mice. 52 , 158 …”

Involvement of Cxcl12a/Cxcr4b Chemokine System in Mediating the Stimulatory Effect of Embryonic Ethanol Exposure on Neuronal Density in Zebrafish Hypothalamus

“…To further explore this phenomenon of increased neurogenesis at lower EtOH doses as it relates to neuroimmune systems in the brain, we focused here on the pro‐inflammatory chemokine Cxcl12 (also known as SDF‐1) and its primary receptor Cxcr4, which are shown to have a major role in processes of neurogenesis, influencing the proliferation, differentiation, and migration of neurons from neuroprogenitor cells shown predominantly in vitro (Hwang et al, 2019). In adult human subjects, EtOH and beer are found to stimulate Cxcr4 expression in peripheral tissue and increase circulating levels of Cxcl12 (Chiva‐Blanch et al, 2014; Poulsen et al, 2019), while prolonged withdrawal or abstinence causes a decrease in Cxcl12 plasma levels (Garcia‐Marchena et al, 2016). Although this EtOH‐induced upregulation of Cxcl12 and Cxcr4 has been recapitulated in vitro (Karim et al, 2013) and in adult rodents (Gil‐Bernabe et al, 2011), there is little evidence describing EtOH’s effects on this chemokine system in the embryo, with only our recent study in the rat providing evidence that prenatal EtOH exposure at a moderate dose stimulates the Cxcl12/Cxcr4 system in neurons and neuroprogenitor cells in the hypothalamus (Chang et al, 2020a).…”