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

Abstract

Acute kidney injury (AKI) is an increasingly common disorder that is strongly linked to short- and long-term morbidity and mortality. During AKI process, macrophages, one of the important immune response cells, can polarize into M1 and M2 subtype from M0 subtype. It is well-known that M1 macrophages play a pro inflammatory role while M2 macrophages play an anti-inflammatory role. Glycoprotein non-metastatic melanoma protein b (Gpnmb) is a glycosylated transmembrane protein highly expressed in numerous cells, including osteoblasts, dendritic cells and macrophages. Gpnmb serves as a negative regulator of inflammation in macrophages and has a protective effect on injuries. In acute kidney injury, the macrophage has been shown diverse roles depending on different phenotype. This study provided gene expression and protein expression evidence that Gpnmb was highly expressed in M2 macrophages in the damaged areas of kidney after ischemia-reperfusion injury. Then, we successful isolated and culture mouse bone marrow-derived macrophages (BMMφ) and found that Gpnmb showed different expression levels in M0, M1 and M2 BMMφ: lowest in M1, highest in M2. After knocking down Gpnmb with si-Gpnmb, BMMφ M2 polarization and secretion of anti-inflammatory cytokines IL-10 and TGF-β were inhibited, while M1 polarization and secretion of proinflammatory cytokines IL-1β and TNF-α were promoted. Moreover, IL-4-STAT6 pathway was involved in the promotion of M2 polarization by Gpnmb. Taken together, Gpnmb may serve as a potential biomarker of AKI and play a protective role against the AKI by modulating the polarization of macrophage.

Keywords: Acute kidney injury; Glycoprotein non-metastatic melanoma protein b (Gpnmb); Macrophages; Marrow-derived macrophages (BMMφ); Polarization.