Calcitonin Gene-Related Peptide Negatively Regulates Alarmin-Driven Type 2 Innate Lymphoid Cell Responses.,Immunity

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Calcitonin Gene-Related Peptide Negatively Regulates Alarmin-Driven Type 2 Innate Lymphoid Cell Responses.
Immunity ( IF 25.5 ) Pub Date : 2019-10-08 , DOI: 10.1016/j.immuni.2019.09.005
Antonia Wallrapp ₁ , Patrick R Burkett ₂ , Samantha J Riesenfeld ₃ , Se-Jin Kim ₂ , Elena Christian ₄ , Raja-Elie E Abdulnour ₅ , Pratiksha I Thakore ₃ , Alexandra Schnell ₁ , Conner Lambden ₄ , Rebecca H Herbst ₃ , Pavana Khan ₅ , Kazutake Tsujikawa ₆ , Ramnik J Xavier ₇ , Isaac M Chiu ₈ , Bruce D Levy ₅ , Aviv Regev ₉ , Vijay K Kuchroo ₄

Affiliation

Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0871, Japan.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

Neuroimmune interactions have emerged as critical modulators of allergic inflammation, and type 2 innate lymphoid cells (ILC2s) are an important cell type for mediating these interactions. Here, we show that ILC2s expressed both the neuropeptide calcitonin gene-related peptide (CGRP) and its receptor. CGRP potently inhibited alarmin-driven type 2 cytokine production and proliferation by lung ILC2s both in vitro and in vivo. CGRP induced marked changes in ILC2 expression programs in vivo and in vitro, attenuating alarmin-driven proliferative and effector responses. A distinct subset of ILCs scored highly for a CGRP-specific gene signature after in vivo alarmin stimulation, suggesting CGRP regulated this response. Finally, we observed increased ILC2 proliferation and type 2 cytokine production as well as exaggerated responses to alarmins in mice lacking the CGRP receptor. Together, these data indicate that endogenous CGRP is a critical negative regulator of ILC2 responses in vivo.

中文翻译：

降钙素基因相关肽负向调节警报素驱动的 2 型先天淋巴细胞反应。

神经免疫相互作用已成为过敏性炎症的关键调节剂，而 2 型先天淋巴细胞 (ILC2) 是介导这些相互作用的重要细胞类型。在这里，我们表明 ILC2 表达神经肽降钙素基因相关肽 (CGRP) 及其受体。在体外和体内，CGRP 均能有效抑制肺 ILC2 驱动的警报素驱动的 2 型细胞因子的产生和增殖。 CGRP 在体内和体外诱导 ILC2 表达程序发生显着变化，减弱警报素驱动的增殖和效应反应。在体内警报素刺激后，ILC 的一个独特子集在 CGRP 特异性基因特征上得分很高，表明 CGRP 调节了这种反应。最后，我们观察到缺乏 CGRP 受体的小鼠 ILC2 增殖和 2 型细胞因子产生增加，以及对警报素的过度反应。总之，这些数据表明内源性 CGRP 是体内 ILC2 反应的关键负调节因子。

更新日期：2019-10-10

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