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

Abstract

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. FASEB J. 33, 9775–9784 (2019). http://www.fasebj.org

ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells

“…While the role of ORAI1 has widely been clarified, the contribution of the other subunits to I CRAC and SOCE emerged only later [ 28 , 33 ]. Thanks to in-depth studies on the immune system, it has elegantly been demonstrated that, in mouse T cells, ORAI2 forms heteromeric channels with ORAI1 and contributes to a reduced Ca 2+ permeation through I CRAC [ 35 , 39 ]. A negative role for ORAI2 on Ca 2+ entry was already postulated following overexpression studies in HEK293 cells [ 67 ].…”

“…Whereas STIM1 and ORAI1 proteins have been deeply investigated [ 32 ], the same does not hold true for STIM2, ORAI2 and ORAI3 [ 28 , 33 ]. Only recently has the ORAI2 functionality in the immune system started to be well understood [ 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Conversely, in the nervous system, the role of SOCE role and its components remain obscure [ 41 , 42 , 43 ].…”

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“…In line with our findings, PTK6 promotes cancer cell aggressiveness ( 38 , 39 ). LRRK2 is also involved in inflammatory response and cell migration ( 40 , 41 ). Taken together, our data suggest that increased LINK-A promotes PTK6- and LRRK2-mediated HIF-1α protein expression and subsequently regulates aggressiveness and inflammation of RA FLSs.…”

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“…LRRK2 is a key regulator protein also in dendritic cells, which are antigen-presenting cells (APC), playing an important role in Treg maturation. In more detail, LRRK2 influences cell migration through the modulation of ORAI2, which cooperates with calcium channels in the regulation of calcium efflux, necessary for cell homeostasis [ 24 ].…”