EMMPRIN: A Novel Regulator of Leukocyte Transmigration into the CNS in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Abstract

Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a member of the Ig superfamily, with various physiological roles including the induction of matrix metalloproteinases (MMPs), leukocyte activation, and tumor progression. In this study, we illustrate a novel involvement of EMMPRIN in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). We found EMMPRIN levels to be upregulated on peripheral leukocytes before onset of EAE clinical signs and on infiltrating leukocytes and resident cells within the CNS in symptomatic mice. In EAE brain sections, EMMPRIN expression was localized with MMP-9 protein and activity. The increased EMMPRIN level was also characteristic of brain samples from MS subjects, particularly in plaque-containing areas. To evaluate the implications of elevated EMMPRIN levels, we treated EAE mice with an EMMPRIN function-blocking antibody and found reduced EAE clinical severity accompanied by decreased CNS parenchymal infiltration of leukocytes. Amelioration of EAE clinical signs by the anti-EMMPRIN antibody was critically dependent on its administration around the period of onset of clinical signs, which is typically associated with significant influx of leukocytes into the CNS. Moreover, the reduction in disease severity in anti-EMMPRINtreated mice was associated with diminished MMP proteolytic activity at the glia limitans, the final barrier before parenchymal infiltration of leukocytes. Together, our results are the first to emphasize a role for EMMPRIN in MS and EAE, whereby EMMPRIN regulates leukocyte trafficking through increasing MMP activity. These results identify EMMPRIN as a novel therapeutic target in MS.

Targeting Extracellular Cyclophilin A Reduces Neuroinflammation and Extends Survival in a Mouse Model of Amyotrophic Lateral Sclerosis

“…The expression of EMMPRIN receptor was substantially higher in ventral horns compared with dorsal horns in nontransgenic mice, with a remarkable increase in mutant SOD1 mice at a symptomatic stage of the disease. Because, at this stage, there is significant motor neuron loss and gliosis, upregulation is also associated with glial cells, as described previously (Agrawal et al, 2011). Therefore, higher expression of EMMPRIN may underlie the toxic effect of extracellular PPIA toward motor neurons by a non-cell-autonomous mechanism.…”

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

“…8C). The increased levels of EMMPRIN + cells observed likely represents the EMMPRIN + lymphocytes infiltrating the CNS; indeed, an increased level of EMMPRIN + T cells entering the CNS with increasing EAE clinical severity was observed in a previous publication (20). EMMPRIN transcript levels may have already leveled off in these infiltrating cells after their activation in the periphery (as was demonstrated in Figs.…”

“…In support, inflammatory perivascular cuffs in the CNS of EAE and MS specimens have highly elevated EMMPRIN expression in many leukocyte subsets (11), and mice treated with anti-EMMPRIN Abs have reduced EAE clinical severity (12,20). To further ascribe importance to EMMPRIN in MS, we evaluated whether established or emerging therapies in MS affect EMMPRIN expression in leukocytes.…”

“…Although it is unclear how all these mechanisms connect, it is supported by the identification of several EMMPRIN-interacting proteins that correspond to these functions such as monocarboxylate transporters (MCTs) (14,15), integrins (16), CD98 (17), cyclophilins (18), and EMMPRIN itself (1,19). Treatment with anti-EMMPRIN Abs reduced EAE clinical severity, the number of perivascular cuffs, and MMP activity (12,20). Perivascular cuffs, which are aggregates of immune cells in the perivascular space of postcapillary venules prior to their entry into the CNS parenchyma, were shown to be enriched for EMMPRIN expression that colocalized with T cells, B cells, and macrophages, and with manifestation of MMP activity (11).…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…A plethora of stimuli concurs to the MMP-9 aberrant activation, namely (a) EMMPRIN, a glycoprotein dys-regulated in the pathology, which promotes secretion from resident or activated microglia cells (Agrawal et al, 2011;Fabriek et al, 2007;Shinto et al, 2011); (b) apoptotic neurons, which secrete MMP-3, the main pro-MMP-9 activator (Kim and ; (c) fibronectin and vitronectin of the basement membrane, which stimulate MMP-9 synthesis by activated microglia cells in a integrin-dependent manner .…”