{Reference Type}: Journal Article
{Title}: Lipid-orchestrated paracrine circuit coordinates mast cell maturation and anaphylaxis through functional interaction with fibroblasts.
{Author}: Taketomi Y;Higashi T;Kano K;Miki Y;Mochizuki C;Toyoshima S;Okayama Y;Nishito Y;Nakae S;Tanaka S;Tokuoka SM;Oda Y;Shichino S;Ueha S;Matsushima K;Akahoshi N;Ishii S;Chun J;Aoki J;Murakami M;
{Journal}: Immunity
{Volume}: 57
{Issue}: 8
{Year}: 2024 Aug 13
{Factor}: 43.474
{DOI}: 10.1016/j.immuni.2024.06.012
{Abstract}: Interaction of mast cells (MCs) with fibroblasts is essential for MC maturation within tissue microenvironments, although the underlying mechanism is incompletely understood. Through a phenotypic screening of >30 mouse lines deficient in lipid-related genes, we found that deletion of the lysophosphatidic acid (LPA) receptor LPA1, like that of the phospholipase PLA2G3, the prostaglandin D2 (PGD2) synthase L-PGDS, or the PGD2 receptor DP1, impairs MC maturation and thereby anaphylaxis. Mechanistically, MC-secreted PLA2G3 acts on extracellular vesicles (EVs) to supply lysophospholipids, which are converted by fibroblast-derived autotaxin (ATX) to LPA. Fibroblast LPA1 then integrates multiple pathways required for MC maturation by facilitating integrin-mediated MC-fibroblast adhesion, IL-33-ST2 signaling, L-PGDS-driven PGD2 generation, and feedforward ATX-LPA1 amplification. Defective MC maturation resulting from PLA2G3 deficiency is restored by supplementation with LPA1 agonists or PLA2G3-modified EVs. Thus, the lipid-orchestrated paracrine circuit involving PLA2G3-driven lysophospholipid, eicosanoid, integrin, and cytokine signaling fine-tunes MC-fibroblast communication, ensuring MC maturation.