The role of Glycoprotein Nonmetastatic Melanoma Protein B in vascular inflammation during infectious challenge

Abstract

Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a transmembrane glycoprotein that has been shown to play an important role in inflammation. GPNMB levels are increased in association with pro-inflammatory conditions, such as lipopolysaccharide exposure. Further, GPNMB is increased in aged endothelial cells, and reduction of GPNMB in mice has been shown to reduce aging and increase lifespan. Thus, we sought to test the hypothesis that reduction in GPNMB would provide a protective phenotype to endothelial cells undergoing bacterial challenge. In order to test this, GPNMB was knocked down in either immortalized or primary human dermal microvascular endothelial cells (HMVECs) using siRNA. The cells were then treated with heat-killed Escherichia coli (HKEC, 3x108 cells/ml), one of the most common pathogens encountered in severe, systemic infections. With immortalized (i)HMVECs, siRNA-treated GPNMB knockdown produced cells appearing more compact and organized when exposed to HKEC as compared to siRNA controls. GPNMB knockdown iHMVECs also showed decreased IL-6 cytokine production after HKEC exposure (93.8 ± 8.1 pg/ml in siRNA controls versus 4.3 ± 0.03 pg/ml in siGPNMB, p < 0.005). Under similar conditions, primary (p)HMVECs exposure to siGPNMB showed no specific morphologic changes. Because GPNMB is also expressed by other cells, we also tested whether exogenous, secreted GPNMB from a non-endothelial source could impact HMVECs during infection. Interestingly, exogenous GPNMB exposure also significantly reduced pHMVEC IL-6 secretion (1372 ± 89 in control cells treated with HKEC versus 672 ± 36 in GPNMB treated cells followed by HKEC, p < 0.0001) during exposure to HKEC. Thus, our data suggests that endogenous GPNMB may be detrimental to endothelial cells depending on their age. Alternatively, exogenous GPNMB may offer protection to endothelial cells under certain conditions. Overall, the role of GPNMB in vascular health appears both age and source specific. Understanding the dynamic role of GPNMB may provide an opportunity to intervene in a GPNMB-specific manner to provide protection to endothelial cells during acute infectious challenge. Grant: R35 GM138191 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.