The glycoprotein GPNMB attenuates astrocyte inflammatory responses through the CD44 receptor

Matthew L Neal,Kevin M Budge,Jason R Richardson,Fayez F Safadi,Alexa M Boyle

doi:10.1186/s12974-018-1100-1

Abstract

BackgroundNeuroinflammation is one of the hallmarks of neurodegenerative diseases, such as Parkinson’s disease (PD). Activation of glial cells, including microglia and astrocytes, is a characteristic of the inflammatory response. Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane glycoprotein that releases a soluble signaling peptide when cleaved by ADAM10 or other extracellular proteases. GPNMB has demonstrated a neuroprotective role in animal models of ALS and ischemia. However, the mechanism of this protection has not been well established. CD44 is a receptor expressed on astrocytes that can bind GPNMB, and CD44 activation has been demonstrated to reduce NFκB activation and subsequent inflammatory responses in macrophages. GPNMB signaling has not been investigated in models of PD or specifically in astrocytes. More recently, genetic studies have linked polymorphisms in GPNMB with risk for PD. Therefore, it is important to understand the role this signaling protein plays in PD.MethodsWe used data mining techniques to evaluate mRNA expression of GPNMB and its receptor CD44 in the substantia nigra of PD and control brains. Immunofluorescence and qPCR techniques were used to assess GPNMB and CD44 levels in mice treated with MPTP. In vitro experiments utilized the immortalized mouse astrocyte cell line IMA2.1 and purified primary mouse astrocytes. The effects of recombinant GPNMB on cytokine-induced astrocyte activation was determined by qPCR, immunofluorescence, and measurement of nitric oxide and reactive oxygen production.ResultsIncreased GPNMB and CD44 expression was observed in the substantia nigra of human PD brains and in GFAP-positive astrocytes in an animal model of PD. GPNMB treatment attenuated cytokine-induced levels of inducible nitric oxide synthase, nitric oxide, reactive oxygen species, and the inflammatory cytokine IL-6 in an astrocyte cell line and primary mouse astrocytes. Using primary mouse astrocytes from CD44 knockout mice, we found that the anti-inflammatory effects of GPNMB are CD44-mediated.ConclusionsThese results demonstrate that GPNMB may exert its neuroprotective effect through reducing astrocyte-mediated neuroinflammation in a CD44-dependent manner, providing novel mechanistic insight into the neuroprotective properties of GPNMB.

Highlights

Neuroinflammation is one of the hallmarks of neurodegenerative diseases, such as Parkinson’s disease (PD)
Increased Glycoprotein non-metastatic melanoma protein B (GPNMB) and CD44 levels in human PD patients and a mouse MPTP model Recently, GPNMB was identified as a potential risk gene for the development of PD, and one study found that a particular Single nucleotide polymorphism (SNP) at the 7p15 chromosomal region associated with altered PD risk led to increased GPNMB expression [18, 19]
We hypothesized that GPNMB would be increased in the substantia nigra of PD patients compared to age-matched controls

Summary

Introduction

Neuroinflammation is one of the hallmarks of neurodegenerative diseases, such as Parkinson’s disease (PD). Parkinson’s disease (PD) is the second most common neurodegenerative disease behind Alzheimer’s disease [1] It is a chronic, progressive disease with severe motor deficits, including resting tremors, bradykinesia, akinesia, and postural instability. Microglia and astrocytes respond to neuronal injury or toxic stimuli by altering cellular morphology and producing increased levels of inflammatory factors, such as pro-inflammatory cytokines. In PD patients and animal models of PD, there is an increased number of activated microglia and astrocytes accompanied by increased release of pro-inflammatory cytokines in the nigrostriatal pathway [3,4,5,6]. Pro-inflammatory cytokine signaling in astrocytes leads to propagation of the inflammatory response and can reduce the ability of this cell type to protect neurons from cell death [7]

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