Integrin/Chemokine Receptor Interactions in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Abstract

Excessive infiltration of leukocytes and the elaboration of inflammatory cytokines are believed to be responsible for the observed damage to neurons and oligodendrocytes during multiple sclerosis (MS). Blocking adhesion molecules or preventing the effects of chemotactic mediators such as chemokines can be exploited to prevent immune cell recruitment to inflamed tissues. An anti-α4 integrin antibody (anti-VLA-4mAb/natalizumab (Tysabri®)) has been used as a treatment for MS and reduces leukocyte influx into the brain. In patients, anti-VLA-4 reduces relapses and disability progression. However, its mechanism of action in the brain is not completely understood. The anti-VLA-4mAB was demonstrated to mobilize hematopoietic progenitor cells. Interestingly, the chemokine SDF-1/CXCL12 and its receptor CXCR4 are also key factors regulating the migration of hematopoietic stem cells. Moreover, studies have revealed a crosstalk between SDF-1/CXCR4 and VLA-4 signaling in regulating cell migration. In this study, we address the effects of anti-VLA-4 on chemokine signaling in the brain during MS. We assessed the ability of anti-VLA-4 to regulate Experimental Autoimmune Encephalomyelitis (EAE) and chemokine/receptor signaling. Preclinical administration of anti-VLA-4 delayed clinical signs of EAE. We found that anti-VLA-4 treatment reduced chemokine expression. In order to further explore the interaction of anti-VLA-4 with chemokine/receptor signaling we used dual color transgenic mice. After EAE induction, the expression of both SDF-1/CXCL12 and CXCR4 receptor was upregulated, treatment with anti-VLA-4 inhibited this effect. The effects of anti-VLA-4 on chemokine signaling in the CNS may be of importance when considering its mechanism of action and understanding the pathogenesis of EAE.

Pattern of CXCR7 Gene Expression in Mouse Brain Under Normal and Inflammatory Conditions

“…Our recent studies showed that SDF-1/CXCL12, synthesized by cells in the inflamed white matter, can induce the migration of transplanted OPCs to demyelinated white matter during EAE (Banisadr et al 2011). The up-regulation of CXCR7 during demyelination, at the peak of EAE, and it’s colocalization by OPCs arguably suggests that CXCR7 can facilitate the migration of OPCs to sites of pathology, via directed expression of SDF-1/CXCL12 on the surface of astrocytes (Banisadr et al 2014) and CNS endothelial cells, therefore, promote myelin repair. In a viral model of demyelination, CXCR4 signaling has been known indispensable for OPC proliferation and enhanced remyelination (Carbajal et al 2011).…”

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

“…NZ is a humanized monoclonal IgG4 antibody against the alpha-4 subunit of very late antigen-4 (VLA4) of α4β1 and α4β7 integrins [280] that are located on the plasma membrane of lymphocytes and monocytes. NZ is effective in RRMS patients and mainly prevents the infiltration of leukocytes into the MS brain [281], but also more specific effects on immune cells and hematopoietic populations in the CNS have been described [282]. Furthermore, NZ has important additional effects on the MS-affected CNS, including a reduction of oxidative stress and LPS-binding protein (LBP) levels [283], as wells as CSF levels of markers for intrathecal inflammation, axonal damage and demyelination [29].…”

Optimizing multiple sclerosis diagnosis: gene expression and genomic association

“…The most significantly enriched functions are related to immune cell trafficking and adhesion. Specifically, the regulatory network including CXCR4, a master regulator having a known role as a stimulator of T‐ and B‐cell proliferation and migration through the endothelium . CXCR4 connects to the downstream CD6 gene encoding the SRCR domain and binding site for activated cell adhesion molecules, and further continues the process of T‐cell activation.…”