Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system.
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.
Schulze-Topphoff
Ulf
U
Cecilie Vogt Klinik, Charité-University Hospital Berlin, Max Delbrueck Center for Molecular Medicine and NeuroCure Research Center, Berlin, Germany.
Prat
Alexandre
A
Prozorovski
Timour
T
Siffrin
Volker
V
Paterka
Magdalena
M
Herz
Josephine
J
Bendix
Ivo
I
Ifergan
Igal
I
Schadock
Ines
I
Mori
Marcelo A
MA
Van Horssen
Jack
J
Schröter
Friederike
F
Smorodchenko
Alina
A
Han
May Htwe
MH
Bader
Michael
M
Steinman
Lawrence
L
Aktas
Orhan
O
Zipp
Frauke
F
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
D020381:Interleukin-17; D043783:Receptor, Bradykinin B1