Previous proteomic and transcriptional analyses of multiple sclerosis lesions1,2,3 revealed modulation of the renin-angiotensin and the opposing kallikrein-kinin pathways. Here we identify kinin receptor B1 (Bdkrb1) as a specific modulator of immune cell entry into the central nervous system (CNS). We demonstrate that the Bdkrb1 agonist R838 (Sar-[D-Phe]des-Arg9-bradykinin) markedly decreases the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in SJL mice4,5,6, whereas the Bdkrb1 antagonist R715 (Ac-Lys-[D-βNal7, Ile8]des-Arg9-bradykinin) resulted in earlier onset and greater severity of the disease. Bdkrb1-deficient (Bdkrb1−/−) C57BL/6 mice7 immunized with a myelin oligodendrocyte glycoprotein fragment, MOG35–55, showed more severe disease with enhanced CNS-immune cell infiltration. The same held true for mixed bone marrow–chimeric mice reconstituted with Bdkrb1−/− T lymphocytes, which showed enhanced T helper type 17 (TH17) cell invasion into the CNS. Pharmacological modulation of Bdkrb1 revealed that in vitro migration of human TH17 lymphocytes across blood-brain barrier endothelium is regulated by this receptor. Taken together, these results suggest that the kallikrein-kinin system is involved in the regulation of CNS inflammation, limiting encephalitogenic T lymphocyte infiltration into the CNS, and provide evidence that Bdkrb1 could be a new target for the treatment of chronic inflammatory diseases such as multiple sclerosis.
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This work was supported by grants from the Deutsche Forschungsgemeinschaft to O.A. (SFB-TRR 43) and F.Z. (GRK 1258/1, SFB-TRR 43, SFB 650), from the Heinrich und Erna Schaufler-Stiftung to O.A., by European Cooperation in Science and Technology (COST), by the Will Foundation and by a grant from the Multiple Sclerosis Society of Canada to A.P. A.P. is a Donald Paty Career Scientist from the Multiple Sclerosis Society of Canada. We thank T. Hohnstein and N. Nowakowski for expert technical assistance and A. Noon for reading the manuscript as a native speaker.
Supplementary Figures 1-6, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 4401 kb)
Modulation of infiltrative T cell behavior by Bdkrb1 engagement (PBS). (MOV 400 kb)
Modulation of infiltrative T cell behavior by Bdkrb1 engagement (R838). (MOV 536 kb)
Modulation of infiltrative T cell behavior by Bdkrb1 engagement (R715). (MOV 318 kb)
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Schulze-Topphoff, U., Prat, A., Prozorovski, T. et al. Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system. Nat Med 15, 788–793 (2009). https://doi.org/10.1038/nm.1980
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