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

Abstract

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 KitW-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.

Modulation of immunity by the secreted phospholipase A2 family

“…Mast cell‐dependent passive and active anaphylactic responses in response to IgE‐dependent or ‐independent stimuli are markedly attenuated in Pla2g3 −/− mice and conversely augmented in PLA2G3 ‐TG mice 52 . This phenotype is mast cell‐autonomous, since mast cell‐deficient Kit W–sh/W–sh mice transferred with Pla2g3 −/− bone marrow‐derived mast cells (BMMCs), or mast cell‐specific Pla2g3‐ deficient mice, also display similar defects in the anaphylactic response 53 . Strikingly, mast cells in Pla2g3 −/− mice are numerically normal but morphologically and functionally immature, with irregular secretory granules containing lower histamine and mast cell‐specific proteases, lower FcεRI expression on cell surface, and lower production of eicosanoids and cytokines, indicating that sPLA 2 ‐III does not merely act as a mast cell activator, but also functions as a regulator of mast cell maturation.…”

Roles of Mast Cells in Cutaneous Diseases

“…In turn, fibroblast-derived PGD 2 causes immature mast cells to differentiate into mature mast cells ( 47 ). Mast-cell-derived sPLA2-III plays a suppressive role in development of acute CHS, but a promotive role in development of irritant-induced contact dermatitis ( 48 ).…”

Regulatory Roles of Phospholipase A2 Enzymes and Bioactive Lipids in Mast Cell Biology

“…In fact, histamine and protease contents in secretory granules, expression of mast cell maturation markers ( e.g ., histidine decarboxylase (histamine synthase), mast cell proteases, and H-PGDS), and FcεRI-dependent and even -independent activation are considerably lower in Pla2g3 –/– mast cells than in Pla2g3 +/+ mast cells. These phenotypes are mast cell-autonomous, since BMMCs from Pla2g3 –/– mice fail to reconstitute the anaphylactic response after their transfer into mast cell-deficient Kit W-sh/W-sh mice, and since mast cell-specific deletion of sPLA 2 -III also leads to similar defects in mast cell maturation and anaphylaxis ( 20 , 21 ). Importantly, the perturbed mast cell maturation and anaphylaxis in Pla2g3 –/– mice are recapitulated in mice lacking lipocalin-type PGD 2 synthase (L-PGDS), which is expressed in stromal fibroblasts, or those lacking the PGD 2 receptor DP1, which is induced in maturing mast cells.…”

“…Furthermore, mast cell-specific Pla2g3 -deficient mice, as well as mast cell-deficient Kit W-sh mice reconstituted with mast cells prepared from global Pla2g3 – /– mice, display a significant reduction of irritant contact dermatitis (ICD) and an aggravation of Th1-dependent CHS ( 21 ). The increased CHS response by sPLA 2 -III deficiency in mast cells depends, at least in part, on the reduced expression of H-PGDS and thereby reduced production of PGD 2 due to immaturity of mast cells.…”

“…The properties and functions of individual PLA 2 s, as revealed by studies using knockout or transgenic mice for individual PLA 2 s in combination with comprehensive lipidomics, have been summarized in current reviews (14,15). Importantly, genetic and pharmacological studies have provided evidence that several intracellular and extracellular PLA 2 s uniquely regulate the maturation and functions of mast cells through driving distinct lipid pathways in vivo (16)(17)(18)(19)(20)(21)(22)(23). These include (i) cPLA 2 a-driven generation of AA metabolites by activated mast cells for propagation or sequestration of allergic inflammation, (ii) PAF-AH2-driven constitutive generation of EPA/DHA metabolites for optimization of mast cell activation, (iii) sPLA 2 -III-driven paracrine PGD 2 circuit for mast cell maturation, (iv) sPLA 2 -IIA-driven modulation of gut microbiota that indirectly affects mast cells, and (v) miscellaneous PLA 2 s whose roles in mast cells are controversial.…”