Anti-inflammatory role of Gpnmb in adipose tissue of mice

Abstract

Obesity can cause a chronic, low-grade inflammation, which is a critical step in the development of type II diabetes and cardiovascular diseases. Inflammation is associated with the expression of glycoprotein nonmetastatic melanoma protein b (Gpnmb), which is mainly expressed by macrophages and dendritic cells. We generated a Gpnmb-knockout mouse line using Crispr-Cas9 to assess the role of Gpnmb in a diet-induced obesity. The absence of Gpnmb did not affect body weight gain and blood lipid parameters. While wildtype animals became obese but remained otherwise metabolically healthy, Gpnmb-knockout animals developed, in addition to obesity, symptoms of metabolic syndrome such as adipose tissue inflammation, insulin resistance and liver fibrosis. We observed a strong Gpnmb expression in adipose tissue macrophages in wildtype animals and a decreased expression of most macrophage-related genes independent of their inflammatory function. This was corroborated by in vitro data showing that Gpnmb was mostly expressed by reparative macrophages while only pro-inflammatory stimuli induced shedding of Gpnmb. The data suggest that Gpnmb is ameliorating adipose tissue inflammation independent of the polarization of macrophages. Taken together, the data suggest an immune-balancing function of Gpnmb that could delay the metabolic damage caused by the induction of obesity.

Single-cell RNA-seq of a soft-tissue sarcoma model reveals the critical role of tumor-expressed MIF in shaping macrophage heterogeneity

“…Expression of metalloproteinases (Mmp9, Mmp12, and Mmp19) and cathepsin-encoding genes (Ctsb, Ctsd, and Ctsl)-associated with remodeling of the extracellular matrix (Qi et al, 2022)-were also enhanced in Cd36/Spp1 M4. Myeloid cells expressing SPP1 have been noted in multiple human cancers for their immunosuppressive properties (Cheng et al, 2021); accordingly, cluster 3 macrophages also expressed high levels of immune-suppressive genes Lgals3 (encoding galectin-3) and Gpnmb, which is upregulated in macrophages upon transforming growth factor b (TGF-b) stimulation (Nickl et al, 2021) and underlies tumorigenic properties of the so-called ''M2''-polarized macrophages, by promoting cancer stem cell maintenance and metastasis via CD44 and interleukin-33 (IL-33) (Liguori et al, 2021).…”

Mechanism of hydroxysafflor yellow A on acute liver injury based on transcriptomics

“…Glycoprotein nonmetastatic melanoma protein b (Gpnmb) contributes to osteoblast differentiation, inflammatory regulation, and tissue remodeling (Li et al, 2010;Abdelmagid et al, 2015;Nickl et al, 2021). Recently, some liver diseases have been associated with the expression of Gpnmb, such as ALI, cirrhosis, and alcohol-associated hepatitis (Onaga et al, 2003;Haralanova-Ilieva et al, 2005;Harris et al, 2022).…”

Glycoprotein Non-Metastatic Protein B (GPNMB): The Missing Link Between Lysosomes and Obesity

“…The phenomenon that GPNMB plays an essential role in decreasing WAT inflammation during obesity by reducing the number of ATMs was absent when GPNMB was over-expressed in adipocytes and macrophages of mutant mice [81]. Whether the discrepancy in the observed phenotype is due to the different high-fat diet (coconut oil [81] versus lard [83]) remains elusive.…”

“…It was found to be increased in a variety of inflammatory diseases such as colitis, renal diseases, different types of cancers, and neurodegenerative disorders 32 33 . In addition, GPNMB was associated with other disorders, such as senescence 34 , vitiligo 35 , glaucoma 35 , myocardial infarction 37 , and atherosclerosis 38 . Mutations in Gpnmb cause hypopigmented lesions and pigmentary glaucoma in mouse models 39 40 41 and recessive and semi-dominant amyloidosis cutis dyschromica in humans 42 43 .…”