We have investigated the remarkable properties of innate immunity 34through studying group 2 innate lymphoid cells (ILC2), an innate lymphocyte lineage that we identified in 2010. 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.ILC2s are unique in their ability to produce low levels of type 2 cytokines at steady-state. However, it was unknown how this constitutive cytokine pro-duction is regulated. We reported that tristetraprolin (TTP/Zfp36), an RNA-binding protein that induces mRNA degradation, is highly expressed in naive ILC2s and downregulated following IL-33 stimulation. In ILC2s from Zfp36-/- mice, constitutive IL-5 production is elevated owing to the stabilization of its mRNA, which results in an increased number of eosinophils in the in-testine. A luciferase assay demonstrated that TTP directly regulates Il5 mRNA stability and that overexpression of TTP markedly suppresses IL-5 production by ILC2s, even under IL-33 stimulation. Collectively, TTP-mediated posttran-scriptional regulation acts as a deterrent of excessive cytokine production in steady-state ILC2s to maintain body homeostasis.ILC2s are tissue-resident cells that play different roles in different organs by sensing environmental factors in their surroundings. Initially, it was thought that ILC2s in bone marrow (BM) are progenitors for systemic ILC2s, which migrate to other organs and acquire effector functions. However, accumulating evidence that ILC2s differentiate in peripheral tissues suggests that BM ILC2s may play a specific role in the BM as a unique effector per se. We demonstrated that BM ILC2s highly express RANKL, a robust cytokine for osteoclast differ-entiation and activation, and that RANKL expression on ILC2s is up-regulated by IL-2 and IL-7. BM ILC2s co-cultured with BMMs in the presence of IL-7 induce the differentiation of TRAP-positive osteoclasts in a RANKL-dependent manner. In contrast, BM ILC2s stimulated with IL-33 down-regulate RANKL expression and convert BMM differentiation into M2 macrophage-like cells rather than osteoclasts by GM-CSF and IL-13 production. These results suggest that ILC2s regulate osteoclast activation and contribute to bone homeostasis in both steady-state and IL-33-induced inflammation.Figure: Posttranscriptional regulation of ILC2 homeostatic function via TTPIL-33 induces a large amount of IL-5 from activated-ILC2s by transcriptional regulation. On the other hand, in steady-state ILC2s, excessive cytokine production is suppressed by TTP-mediated posttranscriptional regula-tion.Recent Major PublicationsHikichi Y, Motomura Y, Takeuchi O, Moro K. Posttran-scriptional regulation of ILC2 homeostatic function via tristetraprolin. J Exp Med 218, e20210181 (2021)Momiuchi Y, Motomura Y, Suga E, Mizuno H, Kikuta J, Morimoto A, Mochizuki M, Otaki N, Ishii M, Moro K. Group 2 innate lymphoid cells in bone marrow regulate osteoclastogenesis in a reciprocal manner via RANKL, GM-CSF and IL-13. Int Immunol 33, 573-585 (2021)Sudo T, Motomura Y, Okuzaki D, Hasegawa T, Yokota T, Ki-kuta J, Ao T, Mizuno H, Matsui T, Motooka D, Yoshizawa R, Nagasawa T, Kanakura Y, Moro K, Ishii M. Group 2 innate lymphoid cells support hematopoietic recovery under stress conditions. J Exp Med 218, e20200817 (2021)Invited presentationsMoro K. “Fibroblast-derived IL-33 causes pulmonary fibrosis via activation of ILC2” The 50th Annual Meeting of the Japanese Society for Immunology (Kyoto, Japan) December 2021Moro K. “Fibroblast-derived IL-33 causes pulmonary fibrosis via activation of ILC2s” British Society for Immu-nology Congress 2021 (Edinburgh, UK/Online) Novem-ber 2021Moro K. “Single-cell analysis and the innate lymphoid cells” The 25th Congress of the Asian Pacific Society of Respirology (Kyoto, Japan/Online) November 2021Moro K. “Single cell RNA sequence analysis in ILC2s-related diseases” The Human Cell Atlas-Asia 2021 meet-ing (Nedlands, Australia/Online) November 2021Moro K. “Group 2 and 3 innate lymphoid cells drive spontaneous pulmonary fibrosis” The 27th International Symposium on Molecular Cell Biology of Macrophages (Osaka, Japan) June 2021Laboratory for Innate Immune SystemsTeam Leader: Kazuyo Moro
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