Chemokines are inflammatory mediators and are a subtype of cytokines that are secreted as chemoattractants, directing the migration of various cells interacting with endothelial cells during inflammation. Serum CXCL10 level is elevated in MS and correlates with T2-weighted MRI lesions. CXCL10 is also increased by IFN-p-1a or IFN-p-1b after 36 h. Levels of CCL2 and CXCL9 were also elevated during MS relapses. Levels of CCL4 and CCL5 were variable and appeared to depend on patient gender and on other forms of therapy [83]. Chemokines, such as MCP-1, contribute to monocyte extravasation across the BBB in MS [84]. Extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) is a chemokine, which supports immune cell trafficking across the endothelium in MS as well as in the EAE model. EMMPRIN is also linked with increased MMP-9 activity and thus may contribute to MS pathogenesis [85, 86]. CXCL13 levels also increase in relapsing MS [87]. This is actually potentially beneficial as it can contribute to neural precursor cell recruitment across the BBB [88]. CXCL13 appears to be an important biomarker of MS (whose presence reflects the BBB’s attempt to repair MS injury) rather than a cause that contributes to pathology; MS therapy does not decrease CXCL13 levels.

Paradoxically, levels of inflammatory but also anti-inflammatory cytokines increase above baseline in inflamed MS lesions and include IFN-y, IL-2, IL-ip, TNF-a, IL-4, IL-10, IL-12/23, and IL-13 [72, 89]. Many of these cytokines can directly modulate endothelial barrier function and change surface activation properties. Plasma and CNS concentrations of TNF-a, IL-1p, receptor activator of NF-kB ligand (RANKL), and C-reactive protein (CRP) are elevated in MS, particularly during flares [90]. IL-1p upregulation in the CNS contributes to BBB dysfunction by inducing nuclear translocation of p-catenin in CECs to repress claudin-5 expression [91]. Although IL-12/23 is elevated in MS, the IL-12/23 blocking antibody, ustekinumab, has so far shown no benefit in MS therapy [92]. IL-12 suppresses VEGFR-3 expression in brain endothelial cells [93], and VEGFR-3 levels correlate with endothelial dysfunction [94] suggesting that VEGFR-3 may contribute to normal endothelial function and are dysregulated in MS, potentially implicating this lymphatic marker in MS.

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