TY - JOUR
T1 - Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions
AU - Occhiuto, Christopher J.
AU - Kammala, Ananth K.
AU - Yang, Canchai
AU - Nellutla, Rithvik
AU - Garcia, Marco
AU - Gomez, Gregorio
AU - Subramanian, Hariharan
N1 - Publisher Copyright:
© Copyright © 2020 Occhiuto, Kammala, Yang, Nellutla, Garcia, Gomez and Subramanian.
PY - 2020/1/21
Y1 - 2020/1/21
N2 - Mast cells are inflammatory immune cells that play an essential role in mediating allergic reactions in humans. It is well-known that mast cell activation is critically regulated by intracellular calcium ion (Ca2+) concentrations. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a G-protein coupled receptor (GPCR) expressed on mast cells that is activated by various ligands, including several FDA approved drugs; consequently, this receptor has been implicated in causing pseudo-allergic reactions in humans. MRGPRX2 activation leads to an increase in intracellular Ca2+ levels; however, the Ca2+ mobilizing mechanisms utilized by this receptor are largely unknown. Previous reports showed that store-operated Ca2+ entry (SOCE) via the calcium sensor, stromal interaction molecule 1 (STIM1), regulates mast cell response induced by the high-affinity IgE receptor (FcεRI). In this study, using complementary pharmacologic and genetic ablation approaches we demonstrate that SOCE through STIM1 promotes MRGPRX2-induced human mast cell response in vitro. Importantly, SOCE also critically modulates MrgprB2 (mouse ortholog of human MRGPRX2) dependent inflammation in in vivo mouse models of pseudo-allergy. Collectively, our data suggests that MRGPRX2/MrgprB2 activation of mast cells is dependent on SOCE via STIM1, and further characterization of the MRGPRX2-SOCE-STIM1 pathway will lead to the identification of novel targets for the treatment of pseudo-allergic reactions in humans.
AB - Mast cells are inflammatory immune cells that play an essential role in mediating allergic reactions in humans. It is well-known that mast cell activation is critically regulated by intracellular calcium ion (Ca2+) concentrations. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a G-protein coupled receptor (GPCR) expressed on mast cells that is activated by various ligands, including several FDA approved drugs; consequently, this receptor has been implicated in causing pseudo-allergic reactions in humans. MRGPRX2 activation leads to an increase in intracellular Ca2+ levels; however, the Ca2+ mobilizing mechanisms utilized by this receptor are largely unknown. Previous reports showed that store-operated Ca2+ entry (SOCE) via the calcium sensor, stromal interaction molecule 1 (STIM1), regulates mast cell response induced by the high-affinity IgE receptor (FcεRI). In this study, using complementary pharmacologic and genetic ablation approaches we demonstrate that SOCE through STIM1 promotes MRGPRX2-induced human mast cell response in vitro. Importantly, SOCE also critically modulates MrgprB2 (mouse ortholog of human MRGPRX2) dependent inflammation in in vivo mouse models of pseudo-allergy. Collectively, our data suggests that MRGPRX2/MrgprB2 activation of mast cells is dependent on SOCE via STIM1, and further characterization of the MRGPRX2-SOCE-STIM1 pathway will lead to the identification of novel targets for the treatment of pseudo-allergic reactions in humans.
KW - MAS-related G-protein coupled receptor-X2 (MRGPRX2)
KW - MrgprB2
KW - mast cells
KW - pseudo-allergic reactions
KW - store-operated calcium entry (SOCE)
KW - stromal interaction molecule 1 (STIM1)
UR - http://www.scopus.com/inward/record.url?scp=85079072712&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85079072712&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2019.03143
DO - 10.3389/fimmu.2019.03143
M3 - Article
C2 - 32038646
AN - SCOPUS:85079072712
SN - 1664-3224
VL - 10
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 3143
ER -