Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74

Heinrichs, Daniel; Knauel, Meike; Offermanns, C.; Berres, Marie‐Luise; Nellen, Andreas; Leng, Lin; Schmitz, Petra; Bucala, Richard; Weber, Christian; Wasmuth, Hermann E.

doi:10.1073/pnas.1107023108

Cited by 137 publications

(143 citation statements)

References 49 publications

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“…Principally, there is a change from expression of proinflammatory cytokines, chemokines, and profibrotic genes, such as thrombospondin-1 (34), to a profile incorporating genes responsible for scar degradation, such as Mmp12 and Mmp9, genes critical for the clearance of cellular debris, and a number of potential antifibrotic pathways, such as Igf1 (35) and CD74/MIF (33). Furthermore, our data expose the limitations of categorizing macrophage populations from an in vivo setting into the widely used but restrictive M1/M2 paradigm.…”

Section: Discussionmentioning

confidence: 99%

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Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis

Ramachandran

Pellicoro

Vernon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

835

947

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Although macrophages are widely recognized to have a profibrotic role in inflammation, we have used a highly tractable CCl 4 -induced model of reversible hepatic fibrosis to identify and characterize the macrophage phenotype responsible for tissue remodeling: the hitherto elusive restorative macrophage. This CD11B hi F4/80 int Ly-6C lo macrophage subset was most abundant in livers during maximal fibrosis resolution and represented the principle matrix metalloproteinase (MMP) -expressing subset. Depletion of this population in CD11B promoter-diphtheria toxin receptor (CD11B-DTR) transgenic mice caused a failure of scar remodeling. Adoptive transfer and in situ labeling experiments showed that these restorative macrophages derive from recruited Ly-6C hi monocytes, a common origin with profibrotic Ly-6C hi macrophages, indicative of a phenotypic switch in vivo conferring proresolution properties. Microarray profiling of the Ly-6C lo subset, compared with Ly-6C hi macrophages, showed a phenotype outside the M1/M2 classification, with increased expression of MMPs, growth factors, and phagocytosis-related genes, including Mmp9, Mmp12, insulin-like growth factor 1 (Igf1), and Glycoprotein (transmembrane) nmb (Gpnmb). Confocal microscopy confirmed the postphagocytic nature of restorative macrophages. Furthermore, the restorative macrophage phenotype was recapitulated in vitro by the phagocytosis of cellular debris with associated activation of the ERK signaling cascade. Critically, induced phagocytic behavior in vivo, through administration of liposomes, increased restorative macrophage number and accelerated fibrosis resolution, offering a therapeutic strategy to this orphan pathological process.

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Section: Discussionmentioning

confidence: 99%

“…Chemokine (C-X3-C) receptor 1 (CX3CR1)] (32) or antifibrotic effects (e.g. Macrophage migration inhibitory factor (MIF) and CD74) (33) were increased (Fig. 5A).…”

Section: Ly-6c Lo Macrophages Show a Characteristic Gene Expression Pmentioning

confidence: 99%

Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis

Ramachandran

Pellicoro

Vernon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

835

947

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“…Many studies (Musil et al, 2011) have reported the participation of various cytokines in the chronic viral hepatitis type B disease course; these cytokines, which include MIF, IL-17, and IL-10, elicit a variety of biological functions such as adhesion, phagocytosis, anti-tumor activity, and nitric oxide production and would therefore play important roles in inflammatory responses. The research conducted by Heinrichs et al (2011) revealed an important role for MIF in pathological liver damage; similarly, the results of our preliminary study (Yu et al, 2012) indicated the participation of MIF in the overall occurrence and development of viral hepatitis type B, liver cirrhosis, liver cancer, and other hepatopathies and that changes in the MIF levels were closely related to the extent of liver tissue damage. Miquel et al (2013) reported that immune tolerance was broken following antiviral therapy with Baraclude ® such that the level of MIF in the liver tissue was initially enhanced and then gradually reduced.…”

Section: Baracludementioning

confidence: 49%

Changes to the migratory inhibitory factor, IL-17, and IL-10 levels in serum from chronic hepatitis B patients and clinical significance following Baraclude® treatment

Yu¹,

Zhang²,

Li³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. This study aimed to determine the relationship between changes in the serum levels of macrophage migratory inhibitory factor (MIF), interleukin (IL) 17, and IL-10 during chronic hepatitis B treatment via Baraclude ® (Bristol-Meyers Squibb). Thirty-six patients with chronic hepatitis B and 24 healthy individuals were selected as the experimental and control groups, respectively, and the serum levels of MIF, IL-17, and IL-10 were measured during the period in which the experimental group was treated with oral Baraclude ® ; meanwhile, the alanine aminotransferase (ALT), hepatitis B virus (HBV) DNA, and HBV marker (M) levels were measured in the experimental group. In the experimental group, the ALT and HBV-DNA levels began to exhibit obvious decreases in week 4, and the MIF and IL-17 levels exhibited obvious increases in week 4 followed by gradual decreases; however, the IL-10 level exhibited an obvious decrease in week 12 and then (2015) increased gradually. These changes were significant when compared with the control group (P < 0.05). In conclusion, Baraclude ® treatment not only actively suppressed HBV but also indirectly balanced the MIF, IL-17, and IL-10 levels and reduced the liver inflammatory response.

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“…Other genes driving the transition to M2 responses include Cd74, its ligand Mif, and Sting (TMEM173). CD74, in addition to its role in MHC class II responses, is the receptor for Mif and a soluble truncated form of Cd74 has been found, which binds Mif and neutralizes its proinflammatory effects (Heinrichs et al 2011). The ratio of CD74 to Mif is associated with the development of autoimmune hepatitis in humans (Assis et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Drug-induced Liver Fibrosis

et al. 2016

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Nevirapine (NVP) is associated with hepatotoxicity in 1-5% of patients. In rodent studies, NVP has been shown to cause hepatic enzyme induction, centrilobular hypertrophy, and skin rash in various rat strains but not liver toxicity. In an effort to understand whether NVP is metabolized differently in a transiently inflamed liver and whether a heightened immune response alters NVPinduced hepatic responses, female brown Norway rats were dosed with either vehicle or NVP alone (75 mg/kg/day for 15 days) or galactosamine alone (single intraperitoneal [ip] injection on day 7 to mimic viral hepatitis) or a combination of NVP (75/ 100/150 mg/kg/day for 15 days) and galactosamine (single 750 mg/kg ip on day 7). Livers were collected at necropsy for histopathology, matrix-assisted laser desorption/ionization imaging mass spectrometry and gene expression. Eight days after galactosamine, hepatic fibrosis was noted in rats dosed with the combination of NVP and galactosamine. No fibrosis occurred with NVP alone or galactosamine alone. Gene expression data suggested a viral-like response initiated by galactosamine via RNA sensors leading to apoptosis, toll-like receptor, and dendritic cell responses. These were exacerbated by NVP-induced growth factor, retinol, apoptosis, and periostin effects. This finding supports clinical reports warning against exacerbation of fibrosis by NVP in patients with hepatitis C.

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Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74

Cited by 137 publications

References 49 publications

Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis

Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis

Changes to the migratory inhibitory factor, IL-17, and IL-10 levels in serum from chronic hepatitis B patients and clinical significance following Baraclude® treatment

Drug-induced Liver Fibrosis

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