RANTES correlates with inflammatory activity and synaptic excitability in multiple sclerosis

Abstract

Background: Alterations of synaptic transmission induced by inflammatory activity have been linked to the pathogenic mechanisms of multiple sclerosis (MS). Regulated upon activation, normal T-cell expressed, and secreted (RANTES) is a pro-inflammatory chemokine involved in MS pathophysiology, potentially able to regulate glutamate release and plasticity in MS brains, with relevant consequences on the clinical manifestations of the disease. Objective: To assess the role of RANTES in the regulation of cortical excitability. Methods: We explored the association of RANTES levels in the cerebrospinal fluid (CSF) of newly diagnosed MS patients with magnetic resonance imaging (MRI) and laboratory measures of inflammatory activity, as well its role in the control of cortical excitability and plasticity explored by means of transcranial magnetic stimulation (TMS), and in hippocampal mouse slices in vitro. Results: CSF levels of RANTES were remarkably high only in active MS patients and were correlated with the concentrations of interleukin-1β. RANTES levels were associated with TMS measures of cortical synaptic excitability, but not with long-term potentiation (LTP)-like plasticity. Similar findings were obtained in mouse hippocampal slices in vitro, where we observed that RANTES enhanced basal excitatory synaptic transmission with no effect on LTP. Conclusion: RANTES correlates with inflammation and synaptic excitability in MS brains.

5-Fluorouracil chemotherapy upregulates cytokines and alters hippocampal dendritic complexity in aged mice

“…RANTES, now given the immunologic designation CCL5, is one of the principal chemotactic agents that induce recruitment of the immune cells to the CNS via interaction with its corresponding receptor CCR5 51 . RANTES receptors are expressed by hippocampal neurons where it modulates calcium signaling and glutamate release 52 . RANTES has been proposed to be neuroprotective.…”

The role of chemokines and chemokine receptors in multiple sclerosis

“…In the research of E. Sindern et al, CCL5 was not detected in the CSF of RR-MS, but CCL5 release in serum was increased [107]. However, in the 2015 study by Mori F et al, including RRMS patients, CCL5 level was higher in CSF in patients than in the control group, and CCL5 increased during MS disease activity [79]. Other than that, one research by Sørensen et al confirmed the presence of elevated CCL5 in cerebrospinal fluid in patients with acute MS and the fact that lymphocytes expressing CCR5 in the active MS lesions of autopsied brain tissue.…”

“…Infiltrating T cells are able to express and secrete chemokine CCL5 [38], but CCL5 is mainly expressed in perivascular cells, vascular endothelial cells and astrocytes [31]. CCL5 is possible to adjust glutamate release and plasticity in the MS brain with associated effects for the disease clinical manifestations [79] and was detected in active demyelinated MS lesions. CCL5 and its receptor CCR5 have strong monocyte chemotaxis [92].…”

“…The expression of CCL5 may be disrupted by gene mutations and downregulation of its receptor CCR5. For example, a genetic polymorphism, ie, a single nucleotide substitution (A to G) at 403 position of the CCL5 gene promoter results in lower expression of CCL5, or in the 303 position of its receptor CCR5 promoter sequence, X32 (32 base pair deletion) of CCR5 gene coding region is associated with a lower MS severity index [79]. Although a significant increase in CCR5 expression has been found in MS patients, it appears that besides the CCR5Δ32 mutation, other haplotypes or polymorphisms, as well as other possible epigenetic and genetic factors, are vital for CCR5 expression in multiple sclerosis patients [37].…”

Blood Biomarkers and 6- to 7-Year Childhood Outcomes Following Neonatal Encephalopathy

“…10 Select studies on neuroinflammatory and neurodegenerative disorders report an association between elevated RANTES levels and aberrant inflammatory T cell migration, 36 synaptic excitability, and neuroinflammation. 37 RANTES' association with synaptic excitability may be important to neuronal signaling and may lead to significant downstream consequences. Preclinical models suggest a neuroprotective role for RANTES as well.…”