日本东京大学Makoto Murakami研究团队发现，脂质调节的旁分泌回路通过与成纤维细胞的功能性相互作用协调肥大细胞的成熟和过敏性休克。相关论文于2024年7月12日在线发表在《免疫》杂志上。

通过对30多种缺乏脂质相关基因的小鼠品系进行表型筛选，研究人员发现，缺失溶血磷脂酸（LPA）受体LPA1，如同缺失磷脂酶PLA2G3、前列腺素D₂（PGD₂）合酶L-PGDS或PGD₂受体DP1一样，会损害肥大细胞（MC）的成熟，从而影响过敏反应。

在机制上，MS分泌的PLA2G3作用于细胞外囊泡（EV），提供溶血磷脂，后者由成纤维细胞来源的autotaxin（ATX）转化为LPA。成纤维细胞的LPA₁通过促进整合素介导的MS-成纤维细胞粘附、IL-33-ST2信号传导、L-PGDS驱动的PGD₂生成以及前馈的ATX-LPA₁扩增，整合了MS成熟所需的多条途径。

由于PLA2G3缺乏导致的MS成熟缺陷可通过补充LPA₁激动剂或PLA2G3修饰的EV来恢复。因此，由PLA2G3驱动的溶血磷脂、类二十烷酸、整合素和细胞因子信号传导组成的脂质协调旁分泌回路精细调节MS与成纤维细胞的通信，从而确保MS的成熟。

据介绍，MC与成纤维细胞的相互作用对于肥大细胞在组织微环境中的成熟至关重要，尽管其潜在机制尚未完全理解。

附：英文原文

Title: Lipid-orchestrated paracrine circuit coordinates mast cell maturation and anaphylaxis through functional interaction with fibroblasts

Author: Yoshitaka Taketomi, Takayoshi Higashi, Kuniyuki Kano, Yoshimi Miki, Chika Mochizuki, Shota Toyoshima, Yoshimichi Okayama, Yasumasa Nishito, Susumu Nakae, Satoshi Tanaka, Suzumi M. Tokuoka, Yoshiya Oda, Shigeyuki Shichino, Satoshi Ueha, Kouji Matsushima, Noriyuki Akahoshi, Satoshi Ishii, Jerold Chun, Junken Aoki, Makoto Murakami

Issue&Volume: 2024-07-12

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.

DOI: 10.1016/j.immuni.2024.06.012

Source: https://www.cell.com/immunity/fulltext/S1074-7613(24)00318-2