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.
摘要:
肥大细胞(MC)与成纤维细胞的相互作用对于组织微环境中的MC成熟至关重要,尽管潜在的机制还不完全清楚。通过对>30个缺乏脂质相关基因的小鼠品系的表型筛选,我们发现溶血磷脂酸(LPA)受体LPA1的缺失,如磷脂酶PLA2G3,前列腺素D2(PGD2)合酶L-PGDS,或PGD2受体DP1,损害MC成熟,从而导致过敏反应。机械上,MC分泌的PLA2G3作用于细胞外囊泡(EV)以提供溶血磷脂,由成纤维细胞衍生的自分泌运动因子(ATX)转化为LPA。然后,成纤维细胞LPA1通过促进整合素介导的MC成纤维细胞粘附来整合MC成熟所需的多种途径,IL-33-ST2信号,L-PGDS驱动PGD2一代,和前馈ATX-LPA1扩增。通过补充LPA1激动剂或PLA2G3修饰的EV,可以恢复由PLA2G3缺乏导致的MC成熟缺陷。因此,涉及PLA2G3驱动的溶血磷脂的脂质协调旁分泌回路,类花生酸,整合素,和细胞因子信号细调MC-成纤维细胞通讯,确保MC成熟。