Leucine-rich repeat kinase 2 regulates mouse dendritic cell migration by ORAI2

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 CA²⁺ concentration in dendritic cells (DCs). DC maturation and migration are governed by the intracellular CA²⁺ concentration, but the related mechanisms whereby LRRK2 regulates DC function and involved CA²⁺ channels are still under investigation. In the previous study, we found that LRRK2^-/- DCs exhibited higher store-operated CA²⁺ entry (SOCE) activity than LRRK2^+/+ DCs. Herein, we ascertained the exact SOCE components by using genetic, pharmacological, and fluorescent approaches. CA²⁺ 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.