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

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Item Type:	Article
Title:	Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system
Creators Name:	Schulze-Topphoff, U., Prat, A., Prozorovski, T., Siffrin, V., Paterka, M., Herz, J., Bendix, I., Ifergan, I., Schadock, I., Mori, M.A., Van Horssen, J., Schroeter, F., Smorodchenko, A., Han, M.H., Bader, M., Steinman, L., Aktas, O. and Zipp, F.
Abstract:	Previous proteomic and transcriptional analyses of multiple sclerosis lesions 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-Arg(9)-bradykinin) markedly decreases the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in SJL mice, whereas the Bdkrb1 antagonist R715 (Ac-Lys-[D-betaNal(7), Ile(8)]des-Arg(9)-bradykinin) resulted in earlier onset and greater severity of the disease. Bdkrb1-deficient (Bdkrb1(-/-)) C57BL/6 mice 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(H)17) cell invasion into the CNS. Pharmacological modulation of Bdkrb1 revealed that in vitro migration of human T(H)17 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.
Keywords:	Brain, Cell Movement, Experimental Autoimmune Encephalomyelitis, Interleukin-17, Bradykinin B1 Receptor, T-Lymphocytes, Th1 Cells, Animals, Mice
Source:	Nature Medicine
ISSN:	1078-8956
Publisher:	Nature Publishing Group
Volume:	15
Number:	7
Page Range:	788-793
Date:	July 2009
Official Publication:	https://doi.org/10.1038/nm.1980
PubMed:	View item in PubMed

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