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

Schulze-Topphoff U., et al. Nature Medicine 15, 788-793 (2009)

Speaker: Chih-Cheng Kang (康智程)                     Time: 13:10-14:00, Dec 23, 2009

Commentator: Dr. Yee-Shin Lin (林以行 老師)     Place: Room 601

Abstract:

Kinin receptor B1 (Bdkrb1) and B2 are two different heterotrimeric G-protein coupled receptors in the kallikrein–kinin system (KKS). The KKS involves in inflammation and control of blood pressure. Binding of des-Arg9-bradykinin to Bdkrb1 regulate the early inflammation through NF-kB pathway. Furthermore, the expression levels of prokallikrein KLKB1, the precursor enzyme can convert into kallikrein that cleaves the kininogens directly to kinins, and neurolysin, which hydrolyzes bradykinin to des-Arg9-bradykinin, were significantly increased in Multiple sclerosis (MS). MS is a chronic autoimmune inflammatory disease characterized by autoreactive T-cells invade the blood brain barrier that lead inflammation and demyelination in the central nervous system (CNS). Therefore, the authors investigated whether Bdkrb1 may contribute to chronic autoimmune neuroinflammation. In the presence study, they discovered that Bdkrb1 was upregulation on T lymphocytes in CNS from a MS patient and from a mouse with mouse experimental autoimmune encephalomyelitis (EAE) of MS. The Bdkrb1 agonist R838 decreases the disease severity, whereas the Bdkrb1 antagonist R715 accelerated disease onset by using EAE mouse model. In addition, using the Bdkrb1 knockout mice to development EAE, Bdkrb1 KO mice had a significantly disease severity with enhanced CNS-immune cell infiltration. By utilizing reciprocal bone marrow transplantation approach between Bdkrb1-deficient and wild-type mice, they found TH17 cell invasion into the CNS was increased in the Bdkrb1-deficient bone marrow grafting mice. Employing migration assay to mimic the cell crossing blood-brain barrier, the migration of TH17 cells was significant reduced after reconstitution of R838, however TH1 was not. This study indicates that the kinin receptor B1 may play a critical role in the regulation of T cell infiltration after central inflammation and provide a new potential therapeutic treatment of kallikrein-kinin system in multiple sclerosis.

References:

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