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

Abstract

Background & aims Macrophage migration inhibitory factor (MIF) is a multi-potent cytokine that contributes to the inflammatory response to injury. MIF is expressed by multiple cell types; however, the cellular source and actions of MIF in alcoholic liver disease (ALD) are not well known. Here we tested the hypothesis that non-myeloid cells, specifically hepatocytes, are an important cellular source of MIF in ALD. Methods MIF expression was measured in HuH7 and differentiated THP-1 cells in response to ethanol. Ethanol-induced liver injury was assessed in C57BL/6 (WT) and Mif−/− bone marrow chimeras. MIF was measured in peripheral and suprahepatic serum, as well as visualized by immunohistochemistry in liver biopsies, from patients with alcoholic hepatitis (AH). Results HuH7 hepatocytes, but not THP-1 macrophages, released MIF in response to challenge with ethanol in culture. In chimeric mice expressing MIF in non-myeloid cells (Mif−/− →WT), chronic ethanol feeding increased ALT/AST, hepatic steatosis, and expression of cytokine/chemokine mRNA. In contrast, chimeric mice not expressing MIF in non-myeloid cells (WT→ Mif−/−) were protected from ethanol-induced liver injury. Immunohistochemical staining of liver biopsies from patients with AH revealed a predominant localization of MIF to hepatocytes. Interestingly, the concentration of MIF in suprahepatic serum, but not peripheral serum, was positively correlated with clinical indicators of disease severity and with an increased risk of mortality in patients with AH. Conclusions Taken together, these data provide evidence that hepatocyte-derived MIF is critical to the pathogenesis of ALD in mice and likely contributes to liver injury in patients with AH.

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

“…Macrophage migration inhibitory factor (MIF), a master immune regulator, also contributes to liver injury in EtOH‐fed mice and correlates with patient mortality in AH (Barnes et al., ; Marin et al., ). MIF is a pluripotent cytokine (Bacher et al., ; Bernhagen et al., ; Calandra et al., ; Leng et al., ) with roles in autoimmune inflammatory disease such as rheumatoid arthritis and systemic lupus erythematosus (SLE; Sreih et al., ) and in infectious disease such as malaria (Awandare et al., ).…”

“…MIF is linked to the progression of ALD via MIF‐dependent cytokine and chemokine activities (Barnes et al., ; Marin et al., ). Mif −/− mice are protected from liver injury and leukocyte recruitment after chronic Lieber–DeCarli EtOH feeding (Barnes et al., ).…”

“…Mif −/− mice are protected from liver injury and leukocyte recruitment after chronic Lieber–DeCarli EtOH feeding (Barnes et al., ). Furthermore, the concentration of MIF in suprahepatic serum, obtained during transjugular liver biopsies, positively correlates to increased liver dysfunction in AH patients, suggesting MIF plays a contributing role to AH (Marin et al., ). The Gao‐Binge (acute‐on‐chronic, National Institute on Alcohol Abuse and Alcoholism [NIAAA] model) model of EtOH feeding was used in the current study as it better recapitulates certain aspects of the phenotype of AH in humans, for example, exacerbated liver injury, inflammation, and neutrophilia, as compared to chronic Lieber–DeCarli EtOH feeding (Bertola et al., ).…”

Hepatocyte-derived IL-10 plays a crucial role in attenuating pathogenicity during the chronic phase of T. congolense infection

“…Notably, hepatocyte-derived MIF was also shown in another model (i.e. alcoholic liver disease) to be a driving force for liver injury [50]. Overall, an interesting picture emerges whereby hepatocytes are a source of two cytokines that counterbalance each other and exert opposing effects during chronic T. congolense infection: MIF attenuates IL-10 production and promotes pathogenicity; while IL-10 keeps the MIF production in check and softens pathogenicity.…”

“…Moreover, the protein and gene expression levels of IL-6 and Mif, two cytokines documented to play a key role in T. congolense-associated pathology (i.e. susceptibility versus tolerance) and liver injury in particular [20,[48][49][50], were drastically increased in hepatocytes from TgAlbCre-IL10 -/mice compared to the other groups. Interestingly, we have shown before that MIF is a key player in T. congolense-associated pathogenicity [20].…”