Neuropeptide CGRP Limits Group 2 Innate Lymphoid Cell Responses and Constrains Type 2 Inflammation

• Published in: Immunity (Cambridge, Mass.) Vol. 51; no. 4; pp. 682 - 695.e6
• Main Authors: Nagashima, Hiroyuki, Mahlakõiv, Tanel, Shih, Han-Yu, Davis, Fred P., Meylan, Francoise, Huang, Yuefeng, Harrison, Oliver J., Yao, Chen, Mikami, Yohei, Urban, Joseph F., Caron, Kathleen M., Belkaid, Yasmine, Kanno, Yuka, Artis, David, O’Shea, John J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2019; Elsevier Limited
• Subjects: Animals; Calcitonin; Calcitonin gene-related peptide; Cells, Cultured; CGRP; Cytokines; Cytokines - metabolism; Data points; Expulsion; Flow cytometry; Gene expression; Homeostasis; host defense; IL-33; Immune response; Immunity, Innate; immunoregulation; Infections; Inflammation; Inflammation - immunology; Inflammatory bowel disease; Innate immunity; innate lymphoid cells; Interleukin 13; Interleukin 5; Interleukin-33 - metabolism; Lymphocytes; Lymphocytes - immunology; Lymphoid cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Mucosa; Neuromedin; Neuropeptides; Neuropeptides - metabolism; Nippostrongylus - physiology; Nippostrongylus brasiliensis; NMU; Receptors, Calcitonin Gene-Related Peptide - genetics; Receptors, Calcitonin Gene-Related Peptide - metabolism; Scholarships & fellowships; Single-Cell Analysis; single-cell RNA-seq; Strongylida Infections - immunology; Th2 Cells - immunology; Transplantation Chimera; host defense; NMU; immunoregulation; neuropeptides; single-cell RNA-seq; cytokines; innate lymphoid cells; CGRP; IL-33; Nippostrongylus brasiliensis
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2019.06.009

Innate lymphocytes maintain tissue homeostasis at mucosal barriers, with group 2 innate lymphoid cells (ILC2s) producing type 2 cytokines and controlling helminth infection. While the molecular understanding of ILC2 responses has advanced, the complexity of microenvironmental factors impacting ILC2s is becoming increasingly apparent. Herein, we used single-cell analysis to explore the diversity of gene expression among lung lymphocytes during helminth infection. Following infection, we identified a subset of ILC2s that preferentially expressed Il5-encoding interleukin (IL)-5, together with Calca-encoding calcitonin gene-related peptide (CGRP) and its cognate receptor components. CGRP in concert with IL-33 and neuromedin U (NMU) supported IL-5 but constrained IL-13 expression and ILC2 proliferation. Without CGRP signaling, ILC2 responses and worm expulsion were enhanced. Collectively, these data point to CGRP as a context-dependent negative regulatory factor that shapes innate lymphocyte responses to alarmins and neuropeptides during type 2 innate immune responses. [Display omitted] •Single-cell analysis reveals heterogeneity of ILC2 responses to N. brasiliensis•Il5hiILC2s express CGRP and its receptor following helminth infection•CGRP modulates type 2 cytokine production by ILC2s induced by alarmin and NMU•CGRP constrains the magnitude of innate type 2 responses following helminth infection Neuronal and immune systems coordinately orchestrate responses at mucosal barriers. Nagashima et al. applied scRNA-seq technology to track type 2 immune responses in worm infection, identifying neuropeptide CGRP as a factor that modulates inflammation. The study suggests that CGRP may be a useful target in type 2 inflammation.