Morimoto Keiko, Baba Yoshihiro, Shinohara Hisaaki, Kang Sujin, Nojima Satoshi, Kimura Tetsuya, Ito Daisuke, Yoshida Yuji, Maeda Yohei, Sarashina-Kida Hana, Nishide Masayuki, Hosokawa Takashi, Kato Yasuhiro, Hayama Yoshitomo, Kinehara Yuhei, Okuno Tatsusada, Takamatsu Hyota, Hirano Toru, Shima Yoshihito, Narazaki Masashi, Kurosaki Tomohiro, Toyofuku Toshihiko, Kumanogoh Atsushi
Department of Immunopathology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Sci Rep. 2016 May 11;6:25738. doi: 10.1038/srep25738.
B-cell receptor (BCR) signaling plays a critical role in B-cell activation and humoral immunity. In this study, we discovered a critical function of leucine-rich repeat kinase 1 (LRRK1) in BCR-mediated immune responses. Lrrk1(-/-) mice exhibited altered B1a-cell development and basal immunoglobulin production. In addition, these mice failed to produce IgG3 antibody in response to T cell-independent type 2 antigen due to defects in IgG3 class-switch recombination. Concomitantly, B cells lacking LRRK1 exhibited a profound defect in proliferation and survival upon BCR stimulation, which correlated with impaired BCR-mediated NF-κB activation and reduced expression of NF-κB target genes including Bcl-xL, cyclin D2, and NFATc1/αA. Furthermore, LRRK1 physically interacted and potently synergized with CARMA1 to enhance NF-κB activation. Our results reveal a critical role of LRRK1 in NF-κB signaling in B cells and the humoral immune response.
B细胞受体（BCR）信号传导在B细胞活化和体液免疫中起着关键作用。在本研究中，我们发现富含亮氨酸重复激酶1（LRRK1）在BCR介导的免疫反应中具有关键功能。Lrrk1基因敲除小鼠表现出B1a细胞发育改变和基础免疫球蛋白产生异常。此外，由于IgG3类别转换重组缺陷，这些小鼠在对2型非T细胞依赖性抗原作出反应时无法产生IgG3抗体。同时，缺乏LRRK1的B细胞在BCR刺激后增殖和存活方面存在严重缺陷，这与BCR介导的NF-κB活化受损以及包括Bcl-xL、细胞周期蛋白D2和NFATc1/αA在内的NF-κB靶基因表达降低相关。此外，LRRK1与CARMA1发生物理相互作用并有力地协同作用，以增强NF-κB活化。我们的结果揭示了LRRK1在B细胞中NF-κB信号传导和体液免疫反应中的关键作用。
