Interactions between Neutrophils, Th17 Cells, and Chemokines during the Initiation of Experimental Model of Multiple Sclerosis

Abstract

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) in which activated T cell and neutrophil interactions lead to neuroinflammation. In this study the expression of CCR6, CXCR2, and CXCR6 in Th17 cells and neutrophils migrating to the brain during EAE was measured, alongside an evaluation of the production of IL-17, IL-23, CCL-20, and CXCL16 in the brain. Next, inflammatory cell subpopulations accumulating in the brain after intracerebral injections of IL-17 or CXCL1, as well as during modulation of EAE with anti-IL-23R or anti-CXCR2 antibodies, were analyzed. Th17 cells upregulate CXCR2 during the preclinical phase of EAE and a significant migration of these cells to the brain was observed. Neutrophils upregulated CCR6, CXCR2, and CXCR6 during EAE, accumulating in the brain both prior to and during acute EAE attacks. Production of IL-17, IL-23, CCL20, and CXCL16 in the CNS was increased during both preclinical and acute EAE. Intracerebral delivery of CXCL1 stimulated the early accumulation of neutrophils in normal and preclinical EAE brains but reduced the migration of Th17 cells to the brain during the preclinical stage of EAE. Modulation of EAE by anti-IL-23R antibodies ameliorated EAE by decreasing the intracerebral accumulation of Th17 cells.

JAM-A and ALCAM are therapeutic targets to inhibit diapedesis across the BBB of CD14+CD16+ monocytes in HIV-infected individuals

“…This may be a consequence of the stoichiometric differences in expression of the junctional proteins between monocytes and T cells. Whereas less implicated in diapedesis across the brain vasculature compared with T cells, neutrophils have been shown to enter into the CNS after infection by other neurotropic viruses [49,50] and during inflammatory states [51][52][53]. In our studies, however, the transmigration of these cells under baseline conditions or in response to CCL2 or CXCL12 was not consistent (data not shown).…”

Th17 Cells Interactions with the Brain Endothelium in Vitro

“…Our previous work on EAE indicated that CXCR2-positive Th17 cells predominate in the CNS during the preclinical phase and Th17 in the symptomatic phase, and that a significant increase in neutrophil accumulation occurs during the preclinical phase [42], which may suggest that CXCL1 plays a role in both neutrophil regulation and Th17 cell attraction into the brain during the development of EAE. The ability of Th17 cells to induce CXCL1 production via IL-17 secretion has been postulated as a pathogenic pathway linking Th17 cells and neutrophils via endothelial secretion of ELR CXC chemokines.…”

Antigen-oriented T cell migration contributes to myelin peptide induced-EAE and immune tolerance

“…Myelin-specific T cells penetrate the blood-brain barrier and the CNS parenchyma initiating demyelination [13]. Despite extensive research on the homing behavior of autoreactive CD4 + T cells, the cellular and molecular mechanisms which guide myelin-specific T cells homing to the CNS are completely unknown [14,15]. Here we…”