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

Abstract

Previous proteomic and transcriptional analyses of multiple sclerosis lesions1,2,3 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-Arg9-bradykinin) markedly decreases the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in SJL mice4,5,6, whereas the Bdkrb1 antagonist R715 (Ac-Lys-[D-βNal7, Ile8]des-Arg9-bradykinin) resulted in earlier onset and greater severity of the disease. Bdkrb1-deficient (Bdkrb1−/−) C57BL/6 mice7 immunized with a myelin oligodendrocyte glycoprotein fragment, MOG35–55, 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 (TH17) cell invasion into the CNS. Pharmacological modulation of Bdkrb1 revealed that in vitro migration of human TH17 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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Figure 1: Morphological and functional evidence for the involvement of the kallikrein-kinin system in autoimmune CNS inflammation.
Figure 2: Bdkrb1 deficiency leads to enhanced EAE pathology.
Figure 3: Bdkrb1 controls the migratory capacities of T cells targeting the CNS.
Figure 4: Bdkrb1 activation primarily targets the invasion of TH17 cells.

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Acknowledgements

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.

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Contributions

F.Z. and M.B. initiated the investigation of EAE in Bdkrb1−/− mice, previously characterized by I.S., M.A.M. and M.B. L.S., M.H.H. and A.P. contributed screens to the investigations. U.S.-T. performed EAE in Bdkrb1−/− mice including immunological read-outs under the supervision of O.A. T.P. and A.S. performed histological analysis. A.P., M.P. and U.S.-T. performed treatment of EAE with Bdkrb1 agonists and antagonists. U.S.-T. initiated EAE in Bdkrb1−/− bone marrow chimeras, and U.S.-T. together with V.S. and M.P. performed these investigations, including immunological analyses. U.S.-T., T.P., F.S. and I.B. investigated Bdkrb1 expression and small GTPase activity pattern in T cells. J.H., V.S. and U.S.-T. performed mouse T cell migration assays using multiphoton microscopy, and I.I. and A.P. performed human TH1 and TH17 cell migration assays. J.V.H. and T.P. performed immunohistochemical analysis of Bdkrb1 expression in tissue from individuals with multiple sclerosis. All authors analyzed the data; F.Z. and O.A. wrote the manuscript with U.S.-T.; F.Z., O.A., A.P., L.S. and M.B. edited the manuscript.

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Correspondence to Frauke Zipp.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1-6, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 4401 kb)

Supplementary Movie 1

Modulation of infiltrative T cell behavior by Bdkrb1 engagement (PBS). (MOV 400 kb)

Supplementary Movie 2

Modulation of infiltrative T cell behavior by Bdkrb1 engagement (R838). (MOV 536 kb)

Supplementary Movie 3

Modulation of infiltrative T cell behavior by Bdkrb1 engagement (R715). (MOV 318 kb)

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Schulze-Topphoff, U., Prat, A., Prozorovski, T. et al. Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system. Nat Med 15, 788–793 (2009). https://doi.org/10.1038/nm.1980

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