Pharmacological inhibition of the chemokine receptor CX3CR1 attenuates disease in a chronic-relapsing rat model for multiple sclerosis.
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.
Innovative Medicines, CNS and Pain Control, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden.
Anna
A
Ridderstad Wollberg
Anders
A
Ericsson-Dahlstrand
Anders
A
Juréus
Petra
P
Ekerot
Sylvia
S
Simon
Maria
M
Nilsson
Stig-Johan
SJ
Wiklund
Anna-Lena
AL
Berg
Mats
M
Ferm
Dan
D
Sunnemark
Rolf
R
Johansson
D000818:Animals; D001921:Brain / Q000378:metabolism*; D000073883:CX3C Chemokine Receptor 1; D002908:Chronic Disease; D004195:Disease Models, Animal; D009103:Multiple Sclerosis / Q000473:pathology*; D051381:Rats; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012008:Recurrence
D000073883:CX3C Chemokine Receptor 1; C516305:CX3CR1 protein, rat; D019707:Receptors, Chemokine
fractalkine receptor; inflammation