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

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.

• Authors: Ulf Schulze-Topphoff, Alexandre Prat, Timour Prozorovski, Volker Siffrin, Magdalena Paterka, Josephine Herz, Ivo Bendix, Igal Ifergan, Ines Schadock, Marcelo A Mori, Jack Van Horssen, Friederike Schröter, Alina Smorodchenko, May Htwe Han, Michael Bader, Lawrence Steinman, Orhan Aktas, Frauke Zipp
• Journal: Nature medicine (Nat Med) Vol. 15 Issue 7 Pg. 788-93 (Jul 2009) ISSN: 1546-170X [Electronic] United States
• PMID: 19561616 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-17
• Receptor, Bradykinin B1

Topics

• Animals
• Brain (pathology)
• Cell Movement
• Encephalomyelitis, Autoimmune, Experimental (etiology, pathology, therapy)
• Interleukin-17 (physiology)
• Mice
• Mice, Inbred C57BL
• Receptor, Bradykinin B1 (agonists, physiology)
• T-Lymphocytes (physiology)
• Th1 Cells (physiology)