Our goal for this year was to report a novel mouse fibrosis model capable 31Externalrisk factors•Smoking•Environmental factors-Asbestos fibers-Silica dust-Coal dust-Metal dusts •Radiation therapy•Medications •Viral infectionsBleomycin-induced (conventionalfibrosis model)Damaged epithelial cellsNeutrophilsT cellsMacrophagesTGFβFibroblastsMyofibroblastsCollagen production•Aging•Autoimmune diseases-Rheumatoid arthritis-Systemic lupus erythematosus -Sjögren'ssyndrome-Systemic sclerosis•Chronic inflammationPulmonary fibrosis-Allergy•Genetic predispositionIfngr1-/-Rag2-/-(Novel fibrosis model)IFNγIL-13FibroblastsInternalrisk factorsTregILC2sRe-activationIL-33Collagen productionof elucidating the pathogenesis of pulmonary fibrosis induced by internal factors. Fibrosis is a complex disease triggered by both external factors (such as smoking and environmental agents) and internal factors (such as aging and autoimmune diseases). Previous studies predominantly utilized bleomycin-induced mouse models to investigate fibrosis. Bleomycin induces DNA damage in epithelial cells, leading to the activation of T cells, neutrophils, and macro-phages, ultimately resulting in TGFβ-dependent fibrosis. However, it has been recognized that this model is not ideal for understanding fibrosis induced by internal factors.We discovered that Ifngr1-/-Rag2-/- mice, which lack the mechanisms to sup-press group 2 innate lymphoid cells (ILC2s), spontaneously developed severe pulmonary fibrosis in an age-dependent manner. Levels of surfactant protein D (SP-D), a common clinical biomarker reflecting disease activity, increased and the saturation of percutaneous oxygen (SpO2) levels significantly decreased in aged mice. In these mice, the IL-33hiIL-13hi ILC2 subpopulation increased dur-ing the disease-onset phase before collagen production commenced. Additional genetic modifications resulting in defects in ILCs or IL-33 in Ifngr1-/-Rag2-/- mice prevented the development of fibrosis, indicating that IL-33-mediated activation of ILC2s is critical for fibrosis. ILC2s were found to directly induce collagen production by fibroblasts in vitro, and pathogenic fibroblasts began producing IL-33 in the chronic phase, presumably establishing a positive feed-back loop between fibroblasts and ILC2s leading to irreversible fibrosis.Finally, the increased expression of IL1RL1 (IL-33R) and IL13, along with decreased expression of IFNGR1 were confirmed in ILC2s from idiopathic pul-monary fibrosis patients, suggesting that dysregulation of ILC2s may also cause endogenous fibrosis in humans.Figure: Activation of ILC2s through reduction of constitutive IFNγ signaling leads to spontane-ous pulmonary fibrosisThe novel fibrosis model we present in this study con-sists of a mouse in which fibrosis is induced by the dele-tion of two genes, Ifngr1 and Rag2. In Ifngr1-/-Rag2-/- mice, ILC2s directly influence fibroblasts, leading to the induction of collagen production. In addition, in the late stages of the disease, fibroblasts show increased IL-33 expression, suggesting that a feedback loop between ILC2s and IL-33 contributes to fibrosis exacerbation.Recent Major PublicationsOtaki N, Motomura Y, Terooatea T, Thomas Kelly S, Mo-chizuki M, Takeno N, Koyasu S, Tamamitsu M, Sugihara F, Kikuta J, Kitamura H, Shiraishi Y, Miyanohara J, Nagano Y, Saita Y, Ogura T, Asano K, Minoda A, Moro K. Activation of ILC2s through constitutive IFNγ signaling reduction leads to spontaneous pulmonary fibrosis. Nat Commun 14, 8120 (2023)Irie M, Kabata H, Sasahara K, Kurihara M, Shirasaki Y, Kamatani T, Baba R, Matsusaka M, Koga S, Masaki K, Miyata J, Araki Y, Kikawada T, Kabe Y, Suematsu M, Yam-agishi M, Uemura S, Moro K, Fukunaga K. Annexin A1 is a cell-intrinsic metalloregulator of zinc in human ILC2s. Cell rep 42, 112610 (2023)Kobayashi T, Moro K. Tissue-Specific Diversity of Group 2 Innate Lymphoid Cells in the Skin. Front Immunol 13, 885642 (2022)Invited presentationsMoro K. “The role of group 2 innate lymphoid cells in chronic disease” The International Congress of Immunol-ogy 2023 Congress (Cape Town, South Africa) November 2023Moro K. “Role of ILC2s in Pulmonary Fibrosis” Cytokine 2023 (Athens, Greece) October 2023Moro K. “Role of ILC2s in Inflammatory Diseases” Finn-ish-Japanese Immunology Symposium (Turku, Finland) August 2023Moro K. “The role of group 2 innate lymphoid cells in ulcerative colitis” World Congress of Basic & Clinical Pharmacology (Glasgow, UK) July 2023Moro K. “Mechanical stress-induced skin barrier ampli-fication by ILC” 11th International Congress of Severe Cutaneous Adverse Reactions (Niigata, Japan) May 2022Laboratory for Innate Immune SystemsTeam Leader: Kazuyo Moro
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