Item Type: | Article |
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Title: | Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system |
Creators Name: | Schulze-Topphoff, U. and Prat, A. and Prozorovski, T. and Siffrin, V. and Paterka, M. and Herz, J. and Bendix, I. and Ifergan, I. and Schadock, I. and Mori, M.A. and Van Horssen, J. and Schroeter, F. and Smorodchenko, A. and Han, M.H. and Bader, M. and Steinman, L. and 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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