JACI 2023 (Kunimura et al.)

DOCK2 regulates MRGPRX2/B2-mediated mast cell degranulation and drug-induced anaphylaxis.

Kunimura K^†, Akiyoshi S, Uruno T, Matsubara K, Sakata D, Morino K, Hirotani K, Fukui Y (^†corresponding author):

The Journal of Allergy and Clinical Immunology 151(6): 1415-1420, 2023.

Background: Drug-induced anaphylaxis is triggered by the direct stimulation of mast cells (MCs) via Mas-related G protein–coupled receptor X2 (MRGPRX2; mouse ortholog MRGPRB2). However, the precise mechanism that links MRGPRX2/B2 to MC degranulation is poorly understood. Dedicator of cytokinesis 2 (DOCK2) is a Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 regulates migration and activation of leukocytes, its role in MCs remains unknown.
Objective: We aimed to elucidate whether—and if so, how—DOCK2 is involved in MRGPRX2/B2-mediated MC degranulation and anaphylaxis.
Methods: Induction of drug-induced systemic and cutaneous anaphylaxis was compared between wild-type and DOCK2-deficient mice. In addition, genetic or pharmacologic inactivation of DOCK2 in human and murine MCs was used to reveal its role in MRGPRX2/B2-mediated signal transduction and degranulation.
Results: Induction of MC degranulation and anaphylaxis by compound 48/80 and ciprofloxacin was severely attenuated in the absence of DOCK2. Although calcium influx and phosphorylation of several signaling molecules were unaffected, MRGPRB2-mediated Rac activation and phosphorylation of p21-activated kinase 1 (PAK1) were impaired in DOCK2-deficient MCs. Similar results were obtained when mice or MCs were treated with small-molecule inhibitors that bind to the catalytic domain of DOCK2 and inhibit Rac activation.
Conclusion: DOCK2 regulates MRGPRX2/B2-mediated MC degranulation through Rac activation and PAK1 phosphorylation, thereby indicating that the DOCK2-Rac-PAK1 axis could be a target for preventing drug-induced anaphylaxis.

https://researchmap.jp/-kunimura-/published_papers/41119008