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

IF 25.5 1区 医学 Q1 IMMUNOLOGY Immunity Pub Date : 2024-07-12 DOI:10.1016/j.immuni.2024.06.012
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
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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.

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脂质协调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
肥大细胞(MC)与成纤维细胞的相互作用是MC在组织微环境中成熟的必要条件,但其基本机制尚不完全清楚。通过对30个缺乏脂质相关基因的小鼠品系进行表型筛选,我们发现溶血磷脂酸(LPA)受体LPA1的缺失与磷脂酶PLA2G3、前列腺素D2(PGD2)合成酶L-PGDS或PGD2受体DP1的缺失一样,都会影响MC的成熟,从而导致过敏性休克。从机制上讲,MC 分泌的 PLA2G3 作用于细胞外囊泡 (EV),以提供溶血磷脂,溶血磷脂在成纤维细胞衍生的自旋素 (ATX) 作用下转化为 LPA。成纤维细胞 LPA1 随后通过促进整合素介导的 MC-成纤维细胞粘附、IL-33-ST2 信号传导、L-PGDS 驱动的 PGD2 生成以及 ATX-LPA1 的前馈放大,整合 MC 成熟所需的多种途径。补充 LPA1 激动剂或 PLA2G3 修饰的 EV 可恢复 PLA2G3 缺乏导致的 MC 成熟缺陷。因此,PLA2G3驱动的溶血磷脂、二十碳六烷酸、整合素和细胞因子信号的脂质协调旁分泌回路可微调MC与成纤维细胞之间的交流,从而确保MC的成熟。
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来源期刊
Immunity
Immunity 医学-免疫学
CiteScore
49.40
自引率
2.20%
发文量
205
审稿时长
6 months
期刊介绍: Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.
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