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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

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-ΒNal 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.

Original languageEnglish (US)
Pages (from-to)788-793
Number of pages6
JournalNature Medicine
Volume15
Issue number7
DOIs
StatePublished - Jul 2009

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system'. Together they form a unique fingerprint.

Cite this