The many faces of EMMPRIN—Roles in neuroinflammation

Abstract

The central nervous system (CNS) is a relatively immune-privileged organ, wherein a well-instated barrier system (the blood-brain barrier) prevents the entry of blood cells into the brain with the exception of regular immune surveillance cells. Despite this tight security immune cells are successful in entering the CNS tissue where they result in states of neuroinflammation, tissue damage and cell death. Various components of the blood-brain barrier and infiltrating cells have been examined to better understand how blood cells are able to breach this secure barrier. Proteases, specifically matrix metalloproteinases (MMP), have been found to be the common culprits in most diseases involving neuroinflammation. MMPs secreted by infiltrating cells act specifically upon targets on various components of the blood-brain barrier, compromising this barrier and allowing cell infiltration into the CNS. Extracellular matrix metalloproteinase inducer (EMMPRIN) is an upstream inducer of several MMPs and is suggested to be the master regulator of MMP production in disease states such as cancer metastasis. EMMPRIN in the context of the CNS is still relatively understudied. In this review we will introduce EMMPRIN, discuss its ligands and roles in non-CNS conditions that can help implicate its involvement in CNS disorders, showcase its expression within the CNS in healthy and disease conditions, elucidate its ligands and receptors, and briefly discuss the emerging roles it plays in various diseases of the CNS involving inflammation.

Importance of N-Glycosylation on CD147 for Its Biological Functions

“…It has many designations across species including human extracellular matrix metalloproteinase inducer (EMMPRIN) [5], hBasigin [6], M6 [7] and HAb18G [8]; rat OX-47 [9] and CE9 [10]; mouse gp42 [11] and basigin-1 [12]; and chicken HT7 [13], neurothelin [14], and 5A11 [15]. Numerous studies have documented the significance of CD147 in various physiological processes, such as spermatogenesis and fertilization, neural network, and retinal development [12,16–18], and in the progression of several diseases including atherosclerosis, rheumatoid arthritis, and infections by malaria parasites and virus [19–22]. The best characterized function of CD147 is its role in tumor metastasis, angiogenesis, and chemoresistance [23–25].…”

Hepatocyte Produced Matrix Metalloproteinases Are Regulated by CD147 in Liver Fibrogenesis

“…Importantly, CD147 is not expressed within the fibrotic septa where there is a predominance of activated HSC [1], [14]. CD147 is a widely-expressed multifunctional, highly glycosylated, cell surface transmembrane protein which is upregulated in many forms of tissue injury associated with inflammation and matrix remodelling [15]–[17]. In multiple extrahepatic organ systems and in inflammatory conditions such as arthritis, CD147 has been shown to regulate MMP production and determine the progression of fibrosis [14], [18]–[24].…”

EMMPRIN Is Secreted by Human Uterine Epithelial Cells in Microvesicles and Stimulates Metalloproteinase Production by Human Uterine Fibroblast Cells

“…6,22,23 Cytokine regulation of EMM-PRIN is supported by EMMPRIN's duel role as an immune modulator 35 by suppressing activated T-cell responses 36 and serving as an anti-inflammatory mediator. 37 Ovarian hormone and cytokine regulated release of EMMPRIN through microvesicle shedding is consistent with communication modality utilized by both reproductive and nonreproductive tissues.…”