CCR2+CCR5+ T Cells Produce Matrix Metalloproteinase-9 and Osteopontin in the Pathogenesis of Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a demyelinating disease of the CNS that is presumably mediated by CD4+ autoimmune T cells. Although both Th1 and Th17 cells have the potential to cause inflammatory CNS pathology in rodents, the identity of pathogenic T cells remains unclear in human MS. Given that each Th cell subset preferentially expresses specific chemokine receptors, we were interested to know whether T cells defined by a particular chemokine receptor profile play an active role in the pathogenesis of MS. In this article, we report that CCR2+CCR5+ T cells constitute a unique population selectively enriched in the cerebrospinal fluid of MS patients during relapse but not in patients with other neurologic diseases. After polyclonal stimulation, the CCR2+CCR5+ T cells exhibited a distinct ability to produce matrix metalloproteinase-9 and osteopontin, which are involved in the CNS pathology of MS. Furthermore, after TCR stimulation, the CCR2+CCR5+ T cells showed a higher invasive potential across an in vitro blood–brain barrier model compared with other T cells. Of note, the CCR2+CCR5+ T cells from MS patients in relapse are reactive to myelin basic protein, as assessed by production of IFN-γ. We also demonstrated that the CCR6−, but not the CCR6+, population within CCR2+CCR5+ T cells was highly enriched in the cerebrospinal fluid during MS relapse (p < 0.0005) and expressed higher levels of IFN-γ and matrix metalloproteinase-9. Taken together, we propose that autoimmune CCR2+CCR5+CCR6− Th1 cells play a crucial role in the pathogenesis of MS.

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

“…43 Although CCR2 expression in the monocytes is an indicator of a proinflammatory M1 phenotype, in T cells CCR2 expression is associated with a stable effector memory T-cell subtype 44 and, in combination with CCR5, has an increased propensity to produce MMP-9. 45 This enhanced expression of CCR2 in the circulating monocytes and T cells suggests a proinflammatory/memory phenotype, and CYP1B1 in these cells could contribute to the expression of CCR2.…”

Natalizumab in progressive MS

“…13,35 Because the intrathecal sources of osteopontin are microglia, macrophages, astrocytes, macrophages, and T cells, while CXCL13 and MMP9 are expressed by cells most likely to be blood-derived leukocytes, and patients with progressive MS have substantial microglia activation in slowly expanding lesions, GM, and NAWM, these findings could indicate that residual inflammation is mainly caused by brain-resident microglia or macrophages. 17,[36][37][38] Whether residual inflammation and tissue damage will decrease further with longer treatment duration or by treatments targeting microglia and macrophages are important questions to be addressed in future studies. The blockage of systemic immune cells by natalizumab could theoretically reduce inflammation necessary for tissue repair and remyelination.…”

CCL2/CCR2-Dependent Recruitment of Th17 Cells but Not Tc17 Cells to the Lung in a Murine Asthma Model

“…The CCL2/CCR2 axis is relevant in various autoimmune diseases, such as multiple sclerosis, autoimmune encephalomyelitis and autoimmune arthritis [38,39,40]. However, the role of the CCL2/CCR2 axis in the migration of Th17 and Tc17 cells to the lung in allergic asthma has not yet been reported.…”