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

doi:10.1038/nm.1980

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

Microbiology-Immunology

Research output: Contribution to journal › Article › peer-review

104 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 language	English (US)
Pages (from-to)	788-793
Number of pages	6
Journal	Nature Medicine
Volume	15
Issue number	7
DOIs	https://doi.org/10.1038/nm.1980
State	Published - Jul 2009

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Biochemistry, Genetics and Molecular Biology(all)

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10.1038/nm.1980

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Schulze-Topphoff, U., Prat, A., Prozorovski, T., Siffrin, V., Paterka, M., Herz, J., Bendix, I., Ifergan, I., Schadock, I., Mori, M. A., Van Horssen, J., Schröter, F., Smorodchenko, A., Han, M. H., Bader, M., Steinman, L., Aktas, O., & Zipp, F. (2009). Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system. Nature Medicine, 15(7), 788-793. https://doi.org/10.1038/nm.1980

@article{215fbfd5beab40dc9289a22198101e70,

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-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.",

author = "Ulf Schulze-Topphoff and Alexandre Prat and Timour Prozorovski and Volker Siffrin and Magdalena Paterka and Josephine Herz and Ivo Bendix and Igal Ifergan and Ines Schadock and Mori, {Marcelo A.} and {Van Horssen}, Jack and Friederike Schr{\"o}ter and Alina Smorodchenko and Han, {May Htwe} and Michael Bader and Lawrence Steinman and Orhan Aktas and Frauke Zipp",

note = "Funding Information: This work was supported by grants from the Deutsche Forschungsgemeinschaft to O.A. (SFB-TRR 43) and F.Z. (GRK 1258/1, SFB-TRR 43, SFB 650), from the Heinrich und Erna Schaufler-Stiftung to O.A., by European Cooperation in Science and Technology (COST), by the Will Foundation and by a grant from the Multiple Sclerosis Society of Canada to A.P. A.P. is a Donald Paty Career Scientist from the Multiple Sclerosis Society of Canada. We thank T. Hohnstein and N. Nowakowski for expert technical assistance and A. Noon for reading the manuscript as a native speaker.",

year = "2009",

month = jul,

doi = "10.1038/nm.1980",

language = "English (US)",

volume = "15",

pages = "788--793",

journal = "Nature Medicine",

issn = "1078-8956",

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Schulze-Topphoff, U, Prat, A, Prozorovski, T, Siffrin, V, Paterka, M, Herz, J, Bendix, I, Ifergan, I, Schadock, I, Mori, MA, Van Horssen, J, Schröter, F, Smorodchenko, A, Han, MH, Bader, M, Steinman, L, Aktas, O & Zipp, F 2009, 'Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system', Nature Medicine, vol. 15, no. 7, pp. 788-793. https://doi.org/10.1038/nm.1980

TY - JOUR

T1 - Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system

AU - Schulze-Topphoff, Ulf

AU - Prat, Alexandre

AU - Prozorovski, Timour

AU - Siffrin, Volker

AU - Paterka, Magdalena

AU - Herz, Josephine

AU - Bendix, Ivo

AU - Ifergan, Igal

AU - Schadock, Ines

AU - Mori, Marcelo A.

AU - Van Horssen, Jack

AU - Schröter, Friederike

AU - Smorodchenko, Alina

AU - Han, May Htwe

AU - Bader, Michael

AU - Steinman, Lawrence

AU - Aktas, Orhan

AU - Zipp, Frauke

N1 - Funding Information: This work was supported by grants from the Deutsche Forschungsgemeinschaft to O.A. (SFB-TRR 43) and F.Z. (GRK 1258/1, SFB-TRR 43, SFB 650), from the Heinrich und Erna Schaufler-Stiftung to O.A., by European Cooperation in Science and Technology (COST), by the Will Foundation and by a grant from the Multiple Sclerosis Society of Canada to A.P. A.P. is a Donald Paty Career Scientist from the Multiple Sclerosis Society of Canada. We thank T. Hohnstein and N. Nowakowski for expert technical assistance and A. Noon for reading the manuscript as a native speaker.

PY - 2009/7

Y1 - 2009/7

N2 - 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.

AB - 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.

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DO - 10.1038/nm.1980

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JO - Nature Medicine

JF - Nature Medicine

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

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