The Role of GPNMB in Inflammation

Abstract

Inflammation is a response to a lesion in the tissue or infection. This process occurs in a specific manner in the central nervous system and is called neuroinflammation, which is involved in neurodegenerative diseases. GPNMB, an endogenous glycoprotein, has been recently related to inflammation and neuroinflammation. GPNMB is highly expressed in macrophages and microglia, which are cells involved with innate immune response in the periphery and the brain, respectively. Some studies have shown increased levels of GPNMB in pro-inflammatory conditions, such as LPS treatment, and in pathological conditions, such as neurodegenerative diseases and cancer. However, the role of GPNMB in inflammation is still not clear. Even though most studies suggest that GPNMB might have an anti-inflammatory role by promoting inflammation resolution, there is evidence that GPNMB could be pro-inflammatory. In this review, we gather and discuss the published evidence regarding this interaction.

Keywords: GPNMB; cancer; inflammation; macrophages; neuroinflammation; protection.

Figure 1

Scheme of GPNMB intracellular signaling in physiological and inflammatory conditions. After ADAM10 cleavage, soluble GPNMB can interact with several receptors, proteins, and other molecules in the cell membrane. Some of these interactions can activate intracellular pathways and lead to changes in other proteins’ expression and consequently in cell response. In basal conditions, GPNMB can interact with NKA and promote neuroprotection against oxidative stress by activation of ERK/MEK and AKT/PI3K pathways. GPNMB can also interact with syndecan-4 and promote inhibition of T cell activation, which is also associated with a resistance of immune checkpoint inhibitors. GPNMB can also promote activation of MMP-2, MMP-3, and MMP-9, M2-macrophage polarization, and a protective role in ischemia-reperfusion injury, but the molecular mechanisms underlying these responses are not known yet. In inflammation, GPNMB seems to have an anti-inflammatory and resolute role by decreasing pro-inflammatory cytokines like TNFα, IL-6, and IL-12 and increasing anti-inflammatory cytokines such as IL-10.