Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system

doi:doi:10.1038/nm.1980

Previous proteomic and transcriptional analyses of multiple sclerosis lesions^1,^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 mice^4,^5,⁶, whereas the Bdkrb1 antagonist R715 (Ac-Lys-[D- beta Nal⁷, 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, MOG_35–55, 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 (T_H17) cell invasion into the CNS. Pharmacological modulation of Bdkrb1 revealed that in vitro migration of human T_H17 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.

Access

Letter

Article Links

Article Tools

Search Pubmed for