Abstract
Mast cells release a variety of mediators, including arachidonic acid (AA) metabolites, to regulate allergy, inflammation, and host defense, and their differentiation and maturation within extravascular microenvironments depend on the stromal cytokine stem cell factor. Mouse mast cells express two major intracellular phospholipases A(2) (PLA(2)s), namely group IVA cytosolic PLA(2) (cPLA(2)α) and group VIA Ca(2+)-independent PLA(2) (iPLA(2)β), and the role of cPLA(2)α in eicosanoid synthesis by mast cells has been well documented. Lipidomic analyses of mouse bone marrow-derived mast cells (BMMCs) lacking cPLA(2)α (Pla2g4a(-/-)) or iPLA(2)β (Pla2g6(-/-)) revealed that phospholipids with AA were selectively hydrolyzed by cPLA(2)α, not by iPLA(2)β, during FcεRI-mediated activation and even during fibroblast-dependent maturation. Neither FcεRI-dependent effector functions nor maturation-driven phospholipid remodeling was impaired in Pla2g6(-/-) BMMCs. Although BMMCs did not produce prostaglandin E(2) (PGE(2)), the AA released by cPLA(2)α from BMMCs during maturation was converted to PGE(2) by microsomal PGE synthase-1 (mPGES-1) in cocultured fibroblasts, and accordingly, Pla2g4a(-/-) BMMCs promoted microenvironmental PGE(2) synthesis less efficiently than wild-type BMMCs both in vitro and in vivo. Mice deficient in mPGES-1 (Ptges(-/-)) had an augmented local anaphylactic response. These results suggest that cPLA(2)α in mast cells is functionally coupled, through the AA transfer mechanism, with stromal mPGES-1 to provide anti-anaphylactic PGE(2). Although iPLA(2)β is partially responsible for PGE(2) production by macrophages and dendritic cells, it is dispensable for mast cell maturation and function.
Highlights
In this study, using bone marrow-derived mast cells (BMMCs) null for cytosolic PLA2 (cPLA2)␣, independent PLA2 (iPLA2), group V secreted PLA2 (sPLA2), or microsomal PGE synthase-1 (mPGES-1), in combination with lipidomic mass spectrometry (MS), we provide the following evidence: (i) cPLA2␣ plays a fundamental role in arachidonic acid (AA)-selective release from BMMCs during Fc⑀RI-mediated activation and even during fibroblast-dependent maturation; (ii) iPLA2 minimally mobilizes phospholipids in mast cells during these processes; (iii) the AA selectively released by cPLA2␣ from BMMCs during maturation is transferred to adjacent fibroblasts to be metabolized to
Expression of cPLA2␣ and iPLA2 in BMMCs—We examined the expression of several intracellular phospholipase A2 (PLA2) enzymes in IL-3maintained immature BMMCs as well as those placed on Swiss
Expression of mRNAs for cPLA2 and cPLA2␥ was barely detectable in BMMCs and was elevated in connective tissue mast cell (CTMC)-like cells (Fig. 1A), whereas that of mRNAs for cPLA2␦, -⑀ and - was below the detection limit under all conditions tested
Summary
Mice deficient in mPGES-1 (Ptges؊/؊) had an augmented local anaphylactic response These results suggest that cPLA2␣ in mast cells is functionally coupled, through the AA transfer mechanism, with stromal mPGES-1 to provide anti-anaphylactic PGE2. In this study, using BMMCs null for cPLA2␣, iPLA2, group V sPLA2, or mPGES-1, in combination with lipidomic mass spectrometry (MS), we provide the following evidence: (i) cPLA2␣ plays a fundamental role in AA-selective release from BMMCs during Fc⑀RI-mediated activation and even during fibroblast-dependent maturation; (ii) iPLA2 minimally mobilizes phospholipids in mast cells during these processes; (iii) the AA selectively released by cPLA2␣ from BMMCs during maturation is transferred to adjacent fibroblasts to be metabolized to PGE2 by mPGES-1, whereas group V sPLA2 in BMMCs fails to participate in this process; and (iv) mPGES-1-driven PGE2 has a negative regulatory role in the allergen-triggered anaphylactic response. IPLA2 was found to play no role in effector functions or phospholipid membrane remodeling in mast cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
