Interrogation of sphingosine-1-phosphate receptor 2 function in vivo reveals a prominent role in the recovery from IgE and IgG-mediated anaphylaxis with minimal effect on its onset

Autocrine stimulation of S1PR2, a receptor for the lipid mediator sphingosine-1-phosphate (S1P), has been implicated in mast cell degranulation to IgE/antigen (Ag) although, paradoxically, its ligand cannot trigger substantial degranulation. Additionally, the in vivo role of S1PR2 in the overall allergic responses is unclear since S1PR2 was reported to be required for the onset of systemic anaphylaxis by IgE/Ag but, in apparent contradiction, also for the recovery from histamine-induced anaphylaxis in a mast cell independent manner. Here, we sought to clarify the role of S1PR2 in mast cell degranulation and in IgE and IgG-mediated anaphylaxis. Lack of S1PR2 reduced IgE/Ag-induced degranulation in in vitro experiments with mucosal mast cells, but had no effect on connective tissue type mast cells. This latter response correlated with a lack of involvement of S1PR2 in the onset of non-lethal IgE/Ag-mediated systemic and cutaneous anaphylaxis. However, S1pr2−/− mice were slow to recover (or did not recover) from FcɛRI-mediated anaphylaxis, an outcome that mirrored their known impairment in histamine clearance due to defective vascular tone. A minor role for S1PR2 in mast cell degranulation was uncovered upon engagement of low affinity receptors for IgG and in the onset of IgG-mediated anaphylaxis. Our findings show that S1PR2 is dispensable for initiating IgE/Ag-mediated connective tissue mast cell degranulation and anaphylaxis, but it is required for normal recovery from anaphylaxis.

► S1PR2 is inconsequential for the initiation of cutaneous and systemic IgE-mediated anaphylaxis.
► S1PR2's predominant role in allergy is in promoting recovery from systemic anaphylaxis.
► S1PR2 has a minor role in mast cell degranulation and in the initiation of anaphylaxis by low occupancy of FcγRIII.
► Both FcɛRI and FcγRIII induce anaphylaxis when high doses of highly cytokinergic IgE are used.
► Agonism, but not antagonism of S1PR2, may hold promise as secondary treatment for systemic anaphylaxis.