We have investigated the remarkable properties of innate immunity 33through studying group 2 innate lymphoid cells (ILC2), an innate lym-phocyte lineage that we identified ten years ago. ILC2 contribute to immune re-sponses by secreting effector cytokines such as IL-5 and IL-13 and regulate the functions of both immune and non-immune cells. ILC2 play a pathogenic role in allergic diseases in barrier tissues including lungs, intestines, and skin. Aim-ing at advancing therapeutic strategies, we dissect how ILC2 form communica-tion networks with other cells and how these networks malfunction in disease. Our lab couples in vitro and in vivo studies with transcriptome and other omics approaches to study the biology of innate immune systems. Our research em-ploys animal disease models, cell biology, single cell sequencing, and imaging.Bone morphogenic protein 7 (BMP7) possess multiple functions, includ-ing regulating adipogenesis. While investigating adipose tissue, we found that ILC2s are abundant in visceral white adipose tissues and that ILC2-derived BMP7 regulates adipocyte differentiation and lipid accumulation. During in vitro culture, fat-derived ILC2s promoted differentiation of fibroblast-like precursors into white adipocytes that contain lipid. Fat-derived ILC2s express BMP2 and BMP7 and induced differentiation of mesenchymal stem cell-like precursors into adipocytes. The fat droplet size was larger in BMP7-conditional knock out mice, suggesting a role of ILC2-derived BMP7 in the induction of brown-adipocyte differentiation. Our study highlighted a crucial role of ILC2s in controlling adipogenesis in the steady state via BMP7 production.Pulmonary fibrosis (PF) is a disease that causes collagen deposition in the lungs. Despite numerous studies on the pathology of PF, the lack of animal mod-els has significantly hampered advancement of our understanding of the disease. We found that 100% of Ifngr1-/-Rag2-/- mice, which lack ILC2 and ILC3 suppres-sion mechanisms, spontaneously developed PF (Figure). Through studying of these mice, we have revealed an indispensable contribution of ILC2 and ILC3 in fibrosis formation. Single-cell RNA-sequence analysis indicated that ILC3 activation occurred during the disease-onset phase in Ifngr1-/-Rag2-/- mice, which triggered subsequent activation of the ILC2 subpopulation. By dissecting patho-genic mechanisms of disease initiation in vitro and in vivo, we have delineated complex networking among ILC2, ILC3 and fibroblasts, which will lead us to develop novel therapeutic options that prevent disease progression.Figure: ILC-mediated pulmonary fibrosis (PF)ILC3s are necessary for ILC2 activation during the PF-onset phase in Ifngr1-/-Rag2-/- mice, and ILC2s directly induced collagen production by fibroblasts during the chronic phase. Enhanced IL-33 production by pathogenic fibroblasts reactivated ILC2s during the chronic phase and caused irreversible fibrosis.Recent Major PublicationsMiyajima Y, Ealey KN, Motomura Y, Mochizuki M, Takeno N, Yanagita M, Economides AN, Nakayama M, Koseki H, Moro K. Effects of BMP7 produced by group 2 innate lymphoid cells on adipogenesis. Int Immunol 32, 407-419 (2020)Wagner M, Ealey KN, Tetsu H, Kiniwa T, Motomura Y, Moro K, Koyasu S. Tumor-Derived Lactic Acid Contributes to the Paucity of Intratumoral ILC2s. Cell Rep 30, 2743-2757.e5 (2020)Kobayashi T, Ricardo-Gonzalez RR, Moro K. Skin-Resident Innate Lymphoid Cells – Cutaneous Innate Guardians and Regulators. Trends Immunol 41, 100-112 (2020)Invited presentationsMoro K. “Mechanism of antigen-independent eo-sinophilic inflammation by ILC2” The Workshop on Eosinophils in Allergy and Related Diseases 2020 (Japan/Online) November 2020Moro K. “The role of IL-4 and IL-13 during asthma” The 60th Annual Meeting of The Japanese Respiratory Soci-ety (Kobe, Japan/Online) September 2020Moro K. “The role of ILC2 in pulmonary fibrosis” Japanese Society of Allergology and World Allergy Organization Joint Congress 2020 (Kyoto, Japan/Online) September 2020Moro K. “ILC2, a potential target for respiratory diseases” The 142nd Meeting of the Japanese Pharmacological Society, Kanto Branch (Chiba, Japan/Online) June 2020Moro K. “ILC2 induce innate IgE secretion by B1 cells via IL-4 production and regulate allergic susceptibility” The 119th Annual Meeting of the Japanese Society of Dermatological Association (Kyoto, Japan/Online) June 2020Laboratory for Innate Immune SystemsTeam Leader: Kazuyo Moro
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