Mast Cell-Specific Deletion of Group III Secreted Phospholipase A₂ Impairs Mast Cell Maturation and Functions

Tissue-resident mast cells (MCs) have important roles in IgE-associated and -independent allergic reactions. Although microenvironmental alterations in MC phenotypes affect the susceptibility to allergy, understanding of the regulation of MC maturation is still incomplete. We previously reported that group III secreted phospholipase A₂ (sPLA₂-III) released from immature MCs is functionally coupled with lipocalin-type prostaglandin D₂ (PGD₂) synthase in neighboring fibroblasts to supply a microenvironmental pool of PGD₂, which in turn acts on the PGD₂ receptor DP1 on MCs to promote their proper maturation. In the present study, we reevaluated the role of sPLA₂-III in MCs using a newly generated MC-specific Pla2g3-deficient mouse strain. Mice lacking sPLA₂-III specifically in MCs, like those lacking the enzyme in all tissues, had immature MCs and displayed reduced local and systemic anaphylactic responses. Furthermore, MC-specific Pla2g3-deficient mice, as well as MC-deficient Kit^W-sh mice reconstituted with MCs prepared from global Pla2g3-null mice, displayed a significant reduction in irritant contact dermatitis (ICD) and an aggravation of contact hypersensitivity (CHS). The increased CHS response by Pla2g3 deficiency depended at least partly on the reduced expression of hematopoietic PGD₂ synthase and thereby reduced production of PGD₂ due to immaturity of MCs. Overall, our present study has confirmed that MC-secreted sPLA₂-III promotes MC maturation, thereby facilitating acute anaphylactic and ICD reactions and limiting delayed CHS response.