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Leucine‐rich repeat kinase 2 regulates mouse dendritic cell migration by ORAI2
Author(s) -
Yan Jing,
Zhao Wenhui,
Gao Chao,
Liu Xia,
Zhao Xiuliang,
Wei Ting,
Gao And Zhaodi
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201802550r
Subject(s) - microbiology and biotechnology , orai1 , kinase , cd86 , chemistry , biology , stim1 , immune system , t cell , endoplasmic reticulum , immunology
The leucine‐rich repeat kinase 2 (LRRK2) is expressed in various immune cells and involved in regulating inflammatory processes. LRRK2 facilitates calcium extrusion exchanger and sodium‐calcium exchanger activity and hence influences intracellular Ca 2+ concentration in dendritic cells (DCs). DC maturation and migration are governed by the intracellular Ca 2+ concentration, but the related mechanisms whereby LRRK2 regulates DC function and involved Ca 2+ channels are still under investigation. In the previous study, we found that LRRK2 −/− DCs exhibited higher store‐operated Ca 2+ entry (SOCE) activity than LRRK2 +/+ DCs. Herein, we ascertained the exact SOCE components by using genetic, pharmacological, and fluorescent approaches. Ca 2+ imaging showed that LRRK2 kinase activity negatively modulated SOCE activity. Moreover, LRRK2 deficiency resulted in an enhanced migration capacity of DCs but had little effect on the maturation process. SOCE is widely known to regulate DC functions; we wanted to dissect the reason why LRRK2 specifically influenced DC migration and therefore silenced ORAI1, ORAI2, and ORAI3, respectively. Transwell assays showed that both ORAI1 and ORAI2 silencing markedly decreased the migration of DCs, but only ORAI1 deficiency influenced the expression of maturation markers CD11c, CD86, and major histocompatibility complex class II. Of note, LRRK2 deficiency increased ORAI2 expression but not that of ORAI1 and ORAI3. Thus, we suggest that LRRK2 modulates DC migration by interfering with ORAI2.—Yan, J., Zhao, W., Gao, C., Liu, X., Zhao, X., Wei, T., Gao, Z. Leucine‐rich repeat kinase 2 regulates mouse dendritic cell migration by ORAI2. FASEB J. 33, 9775–9784 (2019). www.fasebj.org