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

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

doi:10.1016/j.immuni.2024.06.012

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

Immunity. 2024 Aug 13;57(8):1828-1847.e11. doi: 10.1016/j.immuni.2024.06.012. Epub 2024 Jul 12.

Authors

Yoshitaka Taketomi¹, Takayoshi Higashi², Kuniyuki Kano³, Yoshimi Miki², Chika Mochizuki², Shota Toyoshima⁴, Yoshimichi Okayama⁵, Yasumasa Nishito⁶, Susumu Nakae⁷, Satoshi Tanaka⁸, Suzumi M Tokuoka⁹, Yoshiya Oda⁹, Shigeyuki Shichino¹⁰, Satoshi Ueha¹⁰, Kouji Matsushima¹⁰, Noriyuki Akahoshi¹¹, Satoshi Ishii¹¹, Jerold Chun¹², Junken Aoki³, Makoto Murakami¹³

Affiliations

¹ Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
² Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
³ Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8655, Japan.
⁴ Allergy and Immunology Research Project Team, Research Institute of Medical Science, Center for Allergy, and Division of Internal Medicine, Department of Respiratory Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan; Department of Biochemistry & Molecular Biology, Nippon Medical School, Tokyo 113-8602, Japan.
⁵ Allergy and Immunology Research Project Team, Research Institute of Medical Science, Center for Allergy, and Division of Internal Medicine, Department of Respiratory Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan; Department of Allergy and Internal Medicine, Misato Kenwa Hospital, Saitama 341-8555, Japan; Department of Internal Medicine, Division of Respiratory Medicine, Showa University School of Medicine, Tokyo 142-8666, Japan; Advanced Medical Science Research Center, Gunma Paz University Graduate School of Health Sciences, Takasaki 370-0006, Japan.
⁶ Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
⁷ Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8528, Japan.
⁸ Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
⁹ Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
¹⁰ Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.
¹¹ Department of Immunology, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
¹² Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
¹³ Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan. Electronic address: [email protected].

PMID: 39002541
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.

Keywords: anaphylaxis; fibroblast; lipid mediator; lysophosphatidic acid; mast cell; phospholipase A(2); prostaglandin.

MeSH terms

Anaphylaxis* / immunology
Anaphylaxis* / metabolism
Animals
Cell Differentiation
Extracellular Vesicles / metabolism
Fibroblasts* / metabolism
Interleukin-1 Receptor-Like 1 Protein
Interleukin-33 / metabolism
Intramolecular Oxidoreductases / genetics
Intramolecular Oxidoreductases / metabolism
Lipocalins
Lysophospholipids* / metabolism
Mast Cells* / immunology
Mast Cells* / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout*
Paracrine Communication*
Phosphoric Diester Hydrolases* / genetics
Phosphoric Diester Hydrolases* / metabolism
Prostaglandin D2 / metabolism
Receptors, Lysophosphatidic Acid* / genetics
Receptors, Lysophosphatidic Acid* / metabolism
Receptors, Prostaglandin / genetics
Receptors, Prostaglandin / metabolism
Signal Transduction*

Substances

Lysophospholipids
Receptors, Lysophosphatidic Acid
Phosphoric Diester Hydrolases
lysophosphatidic acid
alkylglycerophosphoethanolamine phosphodiesterase
Prostaglandin D2
Interleukin-33
Intramolecular Oxidoreductases
prostaglandin R2 D-isomerase
lysophosphatidic acid receptor 1, mouse
Receptors, Prostaglandin
Il1rl1 protein, mouse
Il33 protein, mouse
Interleukin-1 Receptor-Like 1 Protein
Lipocalins