| Title: | Bruton's tyrosine kinase is a possible therapeutic target in microscopic polyangiitis |
| Authors: | Nakade, Issei Browse this author |
| Tamura, Yuto Browse this author |
| Hashimoto, Fuyu Browse this author |
| Ariza, Yuko Browse this author |
| Hotta, Shingo Browse this author |
| Fujigaya, Hirofumi Browse this author |
| Arai, Suishin Browse this author |
| Taniguchi, Mai Browse this author |
| Ogawa, Hodaka Browse this author |
| Nishibata, Yuka Browse this author |
| Masuda, Sakiko Browse this author →KAKEN DB |
| Nakazawa, Daigo Browse this author →KAKEN DB |
| Tomaru, Utano Browse this author →KAKEN DB |
| Ishizu, Akihiro Browse this author →KAKEN DB |
| Keywords: | MPO-ANCA |
| MPA |
| NETs |
| Btk |
| Btk inhibitor |
| Tirabrutinib |
| Issue Date: | 6-Nov-2023 |
| Publisher: | BMC |
| Journal Title: | Arthritis Research & Therapy |
| Volume: | 25 |
| Start Page: | 215 |
| Publisher DOI: | 10.1186/s13075-023-03201-9 |
| PMID: | 37932784 |
| Abstract: | Background: Bruton's tyrosine kinase (Btk) is an enzyme expressed in leukocytes other than T lymphocytes and plasma cells and involved in B-cell receptor- and Fcγ receptor (FcγR)-mediated signal transduction. Btk inhibitors potentially suppress autoantibody production due to the expected inhibitory ability of B lymphocyte differentiation into antibody-producing plasma cells and reduce FcγR-mediated neutrophil activation, including the release of neutrophil extracellular traps (NETs). Microscopic polyangiitis (MPA) is a systemic small-vessel vasculitis characterized by the pathogenic autoantibody, antineutrophil cytoplasmic antibody (ANCA) that reacts with myeloperoxidase (MPO). MPO and MPO-ANCA immune complex (IC)-induced FcγR-mediated NETs are critically involved in MPA pathogenesis. This study aimed to demonstrate the therapeutic efficacy of the Btk inhibitor tirabrutinib on MPA. Methods: Various doses of tirabrutinib or vehicle were orally administered to Sprague-Dawley rats daily. Four weeks later, the number of peripheral B lymphocytes was counted, and Btk phosphorylation in B lymphocytes was evaluated by flow cytometry. Human peripheral blood neutrophils were stimulated by MPO and anti-MPO antibody ICs (MPO and anti-MPO-ICs), and Btk and its downstream Vav phosphorylation were assessed by western blotting. The effects of tirabrutinib on MPO and anti-MPO-IC-induced NET formation were examined in vitro. Wistar Kyoto rats were immunized with human MPO to induce experimental MPA and given drug-free or tirabrutinib-containing feed (0.0037% or 0.012%) from day 0 or 28. All rats were euthanized on day 42 for serological and histological evaluation. Results: Tirabrutinib inhibited Btk phosphorylation without decreasing B lymphocytes in vivo. Neutrophil Btk and Vav were phosphorylated when stimulated with MPO and anti-MPO-ICs. Tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA in a dose-dependent manner in vivo. Although MPO-ANCA production was not affected, NET-forming neutrophils in the blood were significantly reduced by tirabrutinib. Conclusions: The Btk inhibitor tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA by reducing NET-forming neutrophils but not decreasing MPO-ANCA titer in vivo. This study suggests that Btk is a possible therapeutic target in MPA. |
| Type: | article |
| URI: | http://hdl.handle.net/2115/90705 |
| Appears in Collections: | 保健科学院・保健科学研究院 (Graduate School of Health Sciences / Faculty of Health Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
|
