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Loss of MertK‐Regulated RvD1 Biosynthesis Pathway in Alcohol‐Associated Hepatitis
Author(s) -
Hardesty Josiah,
Zhang Le,
Jacobs Jon,
Warner Jeffrey,
Warner Dennis,
McClain Craig,
Kirpich Irina
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02045
Subject(s) - mertk , alcoholic hepatitis , inflammation , alcoholic liver disease , liver disease , medicine , immunology , cirrhosis , receptor , receptor tyrosine kinase
Background Alcohol‐associated hepatitis (AH) is a clinical disease state that is characterized by severe liver damage and a sustained inflammatory immune response with limited resolution of inflammation. Liver macrophages are key immune cells that maintain and restore liver tissue homeostasis following injury and inflammation. To this end, macrophages synthesize specialized pro‐resolving mediators (SPMs) such as Resolvin D1 (RvD1), which act to resolve liver inflammation and promote liver regeneration. The receptor tyrosine kinase MertK has been demonstrated to regulate macrophage SPM biosynthesis. MertK indirectly promotes ERK phosphorylation, which in turn prevents CAMK2 activation, resulting in 5‐LOX‐mediated synthesis of SPMs. In this study, we hypothesized that loss of MertK‐mediated SPM biosynthesis correlates with increasing AH severity. Methods Liver proteomic and phosphoproteomic analysis was conducted on samples obtained from AH patients (n=6) and patients without ALD as controls (n=12) by LC/MS/MS. Liver RvD1 levels were evaluated by ELISA. A Student's two‐tailed unpaired t‐test was used to determine statistical significance (p<0.05). Linear regression analysis was performed between proteomic data and clinical markers of AH severity (Model End Stage Liver Disease [MELD] and Maddrey Df Scores). Results The AH patients’ average MELD and Maddrey Df scores were 37.2 ± 4.3 and 88.1 ± 20, respectively. First, we observed that RvD1 levels were elevated 2.2‐fold in AH vs controls (p<0.05); however, RvD1 levels declined with increased disease severity (r=‐0.56). Consistent with this, MertK was downregulated 66.7‐fold in AH relative to controls (p<0.05), and phosphorylated ERK1/2 (an effector kinase of MertK) was reduced 1.5‐fold (p<0.05). Further, AT2A2 expression, which is positively regulated by ERK1/2, was decreased 1.2‐fold (p<0.05). AT2A2 reduces cytosolic calcium in macrophages, preventing phosphorylation and activation of the 5‐LOX negative regulator CAMK2. Phosphorylation of CAMK2 was increased 1.33‐fold in AH patients. Correlation analysis revealed that MertK expression was positively correlated with RvD1 levels in AH patients (r=0.62). However, despite a 1.43‐fold increase in 5‐LOX (a key enzyme in SPM synthesis), it was negatively correlated with RvD1 levels (r=‐0.66), suggesting alterations in 5‐LOX activity. Conclusion MertK expression is lost in AH, along with altered downstream SPM biosynthesis. Loss of MertK may reduce SPM biosynthesis, thereby exacerbating AH and altering the resolution of inflammation and restoration of liver tissue homeostasis.