Glycoprotein Nonmetastatic Melanoma B (Gpnmb)-Positive Macrophages Contribute to the Balance between Fibrosis and Fibrolysis during the Repair of Acute Liver Injury in Mice

Abstract

Background and aimsGlycoprotein nonmetastatic melanoma B (Gpnmb), a transmembrane glycoprotein that is expressed in macrophages, negatively regulates inflammation. We have reported that Gpnmb is strongly expressed in the livers of rats fed a choline-deficient, L-amino acid-defined (CDAA) diet. However, the role of macrophage-expressed Gpnmb in liver injury is still unknown. This study aimed to clarify the characteristics of infiltrating macrophages that express Gpnmb, and the involvement of Gpnmb in the repair process in response to liver injury.MethodsC57BL/6J, DBA/2J [DBA] and DBA/2J-Gpnmb+ [DBA-g+] mice were treated with a single intraperitoneal injection of carbon tetrachloride (CCl4) at a dose of 1.0 mL/kg body weight. Mice were sacrificed at predetermined time points, followed by measurement of serum alanine aminotransferase (ALT) levels and histological examination. Expression of Gpnmb, pro-/anti-inflammatory cytokines, and profibrotic/antifibrotic factors were examined by quantitative RT-PCR and/or Western blotting. Immunohistochemistry, fluorescent immunostaining and flow cytometry were used to determine the expression of Gpnmb, CD68, CD11b and α-SMA, phagocytic activity, and the presence of apoptotic bodies. We used quantitative RT-PCR and ELISA to examine TGF-β and MMP-13 expression and the concentrations and supernatants of isolated infiltrating hepatic macrophages transfected with siGpnmb.ResultsIn C57BL/6J mice, serum ALT levels increased at two days after CCl4 injection and decreased at four days. Gpnmb expression in the liver was stimulated four days after CCl4 injection. Histological examination and flow cytometry showed that Gpnmb-positive cells were almost positive for CD68-positive macrophages, contained engulfed apoptotic bodies and exhibited enhanced phagocytic activity. Isolated infiltrating hepatic macrophages transfected with siGpnmb showed high MMP-13 secretion. There was no significant difference in the magnitude of CCl4-induced liver injury between DBA-g+ and DBA mice. However, hepatic MMP-13 expression, as well as α-SMA expression and collagen production, increased significantly in DBA-g+ compared with DBA mice.ConclusionsGpnmb-positive macrophages infiltrate the liver during the recovery phase of CCl4–induced acute liver injury and contribute to the balance between fibrosis and fibrolysis in the repair process following acute liver injury.

Adverse left ventricular remodeling by glycoprotein nonmetastatic melanoma protein B in myocardial infarction

“…6. MMP9 up‐regulation was significantly attenuated in the GPNMB Mut mice, which is in good agreement with literature showing that GPNMB up‐regulates MMP9 (3, 41, 42). In contrast, TIMP‐1 expression was not significantly different between the strains.…”

“…However, inherent differences in the models used, peritoneal macrophage reaction to LPS injection, and autoimmune reactions compared with our MI model might explain these outcomes. Other researchers could not reproduce the anti‐inflammatory role of GPNMB or assign other primary functions to GPNMB expressed in macro‐phages (11, 16, 42, 45). Although GPNMB is a regulator of inflammation in some diseases, its inflammatory function is not responsible for the GPNMB effects we observed in the infarcted heart.…”

“…In a liver fibrosis model, transgenic overexpression of GPNMB in hepatocytes on top of GPNMB up‐regulation in unidentified cells led to less collagen expression in rats (14). In contrast, after liver injury, GPNMB Mut mice were shown recently to have reduced collagen deposition in comparisonwithGPNMB WT mice (42). Although in this study we found no quantitative differences in collagen deposition between GPNMB WT and Mut mouse hearts, qualitative changes might exist, such as amount of collagen cross‐linking, which affects the tensile strength of the ECM and passive tension (stiffness) of LV.…”

Glycoprotein non-metastatic melanoma protein b (Gpnmb) is highly expressed in macrophages of acute injured kidney and promotes M2 macrophages polarization

“…Recent studies have demonstrated that Gpnmb expressed in macrophages functions as a feedback regulator of pro-inflammatory responses [20]. In CCl4-induced acute liver injury, Gpnmb is expressed in infiltrating hepatic macrophage and modulate the balance between fibrosis and fibrolysis [14]. Medeleine et al reported that increased Gpnmb expression was observed in monocyte and macrophages from uremic (the end-stage renal disease) patients [22].…”

“…Gpnmb transgenic rats that over-express Gpnmb in liver cells showed that Gpnmb attenuates the development of hepatic fibrosis [13]. Gpnmb-positive macrophages infiltrate the liver during the recovery phase of CCl4-induced acute liver injury and contribute to the balance between fibrosis and fibrolysis in the repair process following acute liver injury [14]. Thus, it seems that Gpnmb may promote proliferation and differentiation and inhibit immunocyte activation, inflammation and fibrosis.…”