Pharmacological inhibition of the chemokine receptor CX3CR1 attenuates disease in a chronic-relapsing rat model for multiple sclerosis

Significance Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS) causing paralysis. The most effective treatments for MS aim to block infiltration of inflammatory cells to the brain. However, severe side effects related to the broad-acting specificity of these treatments exist. AZD8797, a unique inhibitor of the chemokine receptor CX3CR1, provides inhibition of subpopulations of peripheral leukocytes with potential for a beneficial effect: side effect ratio. We provide evidence that blocking this receptor results in reduced paralysis, inflammation, and degeneration in the CNS in a disease model for MS. Furthermore, CX3CR1 expression analysis in the MS brain strengthens the evidence for CX3CR1 as a new target for the treatment of MS. One hallmark of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is infiltration of leukocytes into the CNS, where chemokines and their receptors play a major mediatory role. CX3CR1 is a chemokine receptor involved in leukocyte adhesion and migration and hence a mediator of immune defense reactions. The role of CX3CR1 in MS and EAE pathogenesis however remains to be fully assessed. Here, we demonstrate CX3CR1 mRNA expression on inflammatory cells within active plaque areas in MS brain autopsies. To test whether blocking CNS infiltration of peripheral leukocytes expressing CX3CR1 would be a suitable treatment strategy for MS, we developed a selective, high-affinity inhibitor of CX3CR1 (AZD8797). The compound is active outside the CNS and AZD8797 treatment in Dark Agouti rats with myelin oligodendrocyte glycoprotein-induced EAE resulted in reduced paralysis, CNS pathology, and incidence of relapses. The compound is effective when starting treatment before onset, as well as after the acute phase. This treatment strategy is mechanistically similar to, but more restricted than, current very late antigen-4–directed approaches that have significant side effects. We suggest that blocking CX3CR1 on leukocytes outside the CNS could be an alternative approach to treat MS.