title: 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: Cecilie Vogt Klinik, Charité-University Hospital Berlin, Max Delbrueck Center for Molecular Medicine and NeuroCure Research Center, Berlin, Germany.
authors: Ulf
authors: U
authors: Schulze-Topphoff
authors: Alexandre
authors: A
authors: Prat
authors: Timour
authors: T
authors: Prozorovski
authors: Volker
authors: V
authors: Siffrin
authors: Magdalena
authors: M
authors: Paterka
authors: Josephine
authors: J
authors: Herz
authors: Ivo
authors: I
authors: Bendix
authors: Igal
authors: I
authors: Ifergan
authors: Ines
authors: I
authors: Schadock
authors: Marcelo A
authors: MA
authors: Mori
authors: Jack
authors: J
authors: Van Horssen
authors: Friederike
authors: F
authors: Schröter
authors: Alina
authors: A
authors: Smorodchenko
authors: May Htwe
authors: MH
authors: Han
authors: Michael
authors: M
authors: Bader
authors: Lawrence
authors: L
authors: Steinman
authors: Orhan
authors: O
authors: Aktas
authors: Frauke
authors: F
authors: Zipp
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D002465:Cell Movement; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology* / Q000473:pathology / Q000628:therapy; D020381:Interleukin-17 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D043783:Receptor, Bradykinin B1 / Q000819:agonists / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D018417:Th1 Cells / Q000502:physiology
chemical_list: D020381:Interleukin-17; D043783:Receptor, Bradykinin B1