Role of MIF in coordinated expression of hepatic chemokines in patients with alcohol-associated hepatitis

Abstract

Background: The chemokine system of ligands and receptors is implicated in the progression of Alcohol-associated hepatitis (AH). Finding upstream regulators could lead to novel therapies. Methods: The coordinated expression of chemokines in livers of healthy controls (HC) and patients with AH in two distinct cohorts of patients with various chronic liver diseases. Studies in cultured hepatocytes and in tissue-specific knockouts were used for mechanistic insight into a potential upstream regulator of chemokine expression in AH.Results: Selected C-X-C chemokine members of the Interleukin 8 (IL8) chemokine family and C-C chemokine CCL20 were highly associated with AH compared to HC, but not in patients with liver diseases of other etiologies (NAFLD or HCV). Our previous studies implicate Macrophage migration inhibitory factor (MIF) as a pleiotropic cytokine/chemokine with the potential to coordinately regulate chemokine expression in AH. LPS-stimulated expression of multiple chemokines in cultured hepatocytes was dependent on MIF. Gao-binge ethanol feeding to mice induced a similar coordinated chemokine expression in livers of wild-type mice; this was prevented in hepatocyte-specific Mif knockout (Mif ΔHep ) mice. Conclusion:This study demonstrates that patients with AH exhibit a specific, coordinately expressed chemokine signature and hepatocyte-derived MIF might drive this inflammatory response.

Pathogenesis of Alcohol-Associated Liver Disease

“…233 It is an integral component of the host antimicrobial alarm system and stress response that induces the proinflammatory functions of immune cells. 232,[234][235][236] Recent studies report higher circulating and hepatic expression of MIF in ALD patients and EtOH-fed rodents. [236][237][238][239] Others report that MIFdeficient mice are more resistant to ALD development.…”

“…232,[234][235][236] Recent studies report higher circulating and hepatic expression of MIF in ALD patients and EtOH-fed rodents. [236][237][238][239] Others report that MIFdeficient mice are more resistant to ALD development. These findings indicate that MIF-directed therapies may likely offer new treatment opportunities for ALD.…”

Alcohol-Related Liver Disease: An Overview on Pathophysiology, Diagnosis and Therapeutic Perspectives

“…The administration of a short lipopeptide (i.e., pepducin ′x1/2pal-i1′) that targets CXCR1/2 markedly attenuated fully established ALD in mice [ 193 ], thus showing the potential of CXCR1/2 blockade for the treatment of ALD. Likewise, the gene expression and serum levels of CCL20, the only chemokine ligand of CCR6, strongly correlated with the severity of AH and gene silencing, significantly ameliorated lipopolysaccharide (LPS)-induced inflammation and liver injury [ 192 , 199 ]. Given the contribution of chemokine–chemokine receptors toward the inflammatory milieu, numerous other chemokines may also participate in the pathogenesis of ALD including CXCL5, CXCL6, Gro-α, and IL-18, establishing their potential value as new biomarkers and/or therapeutic targets for ALD [ 11 , 20 , 191 , 200 ].…”

Role of the chemokine system in liver fibrosis: a narrative review

“…Despite chemokines being intrinsic to immune cell/leukocyte trafficking and inflammation, they are produced by a spectrum of cells within the liver, from resident macrophages to non-immune hepatic epithelial cells like hepatocytes, sinusoidal epithelial cells, cholangiocytes, as well as HSCs and fibroblasts ( 10 ). Preclinical experimental models of liver injury show that most cell types can express and release chemokines in an attempt to resolve cellular injury or toxic insult ( 9 , 17 , 18 ).…”

“…An atypical chemokine is included in this list, macrophage migration inhibitory factor (MIF) ( 30 , 31 ). MIF is a pleiotropic cytokine/chemokine which can interact with CXCRs to promote leukocyte chemotaxis, but our understanding of MIF’s role in liver disease has evolved over the past decade of research ( 18 , 32 – 36 ). The role of MIF in fibrosis is somewhat controversial, as studies in genetic knockout models reported contrasting roles for MIF in fibrosis.…”