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Title: Neuropeptide CGRP limits group 2 innate lymphoid cell responses and constrainst type 2 inflammation

Author
item NAGASHIMA, HIROYUKI - National Institute On Aging (NIA, NIH)
item MAHLAKOIV, T - National Institute On Aging (NIA, NIH)
item SHIH, HAN-YU - National Institute On Aging (NIA, NIH)
item DAVIS, FRED - National Institute On Aging (NIA, NIH)
item MEYLAN, FRANCOISE - National Institute On Aging (NIA, NIH)
item HUANG, YUEFENG - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item HARRISON, OLIVER - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item YAO, CHEN - National Institute On Aging (NIA, NIH)
item MIKAMI, YOHEI - National Institute On Aging (NIA, NIH)
item Urban, Joseph
item CARON, KATHLEEN - University Of North Carolina
item BELKAID, YASMINE - National Institutes Of Health (NIH)
item KANNO, YUKA - National Institutes Of Health (NIH)
item ARTIS, D - New York University
item O'SHEA, JOHN - National Institutes Of Health (NIH)

Submitted to: Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/25/2019
Publication Date: 10/15/2019
Citation: Nagashima, H., Mahlakoiv, T., Shih, H., Davis, F.P., Meylan, F., Huang, Y., Harrison, O., Yao, C., Mikami, Y., Urban Jr, J.F., Caron, K., Belkaid, Y., Kanno, Y., Artis, D.C., O'Shea, J.J. 2019. Neuropeptide CGRP limits group 2 innate lymphoid cell responses and constrains type 2 inflammation. Immunity. 51(4):682-695e6. https://doi.org/10.1016/j.immuni.2019.06.009.
DOI: https://doi.org/10.1016/j.immuni.2019.06.009

Interpretive Summary: Mucosal tissues that line the intestines and lungs are highly innervated, and there is evidence that nerves can regulate immune cells that assist in early responses to infection. It has recently been reported that mucosal neurons produce a messenger peptide called neuromedin U (NMU) that activates a class of innate lymphoid cells (ILC2) that responds to parasitic infection and influence allergy. The current study now demonstrates that NMU and a class of molecules that act as alarming messengers combined to regulate the physiological interplay at the mucosal surface andassure that there is an adequate response to infection without an exacerbated inflammatory response. This information is important to clinicians that require therapeutic tools to control allergic disease and to livestock producers that need novel strategies to eliminate parasitic infections that reduce efficient animal production and compromise animal health. The fact that the interplay is at the intestinal barrier suggests that nutrition can influence the outcome of these factors to provide improved health for both humans and livestock through the diet.

Technical Abstract: Neuropeptides including neuromedin U (NMU) and calcitonin gene Neuropeptides, including neuromedin U (NMU) and calcitonin related peptide (CGRP), act on group 2 innate lymphoid cells (ILC2) to regulate mucosal inflammatory responses. Herein, we show that CGRP counters the actions of the alarmin IL-33 and NMU by altering chromatin accessibility and transcriptomic output. CGRP limits IL-33 and NMU-induced proliferation of ILC2 in vitro and limits IL-33-induced pulmonary inflammation in vivo. CGRP acts on ILC2 to generate cAMP and limits the actions of NMU which signals via Gaq. Single cell sequencing revealed that during Nippostrongylus brasiliensis infection, a subset of lung ILC2 and Th2 cells produce CGRP transcript. The dynamic transition of gene expression modules representing CGRP, NMU and IL-33 signals in ILC2 was observed during helmingh infection, indicating physiological interplay of neuropeptides and alarmin in modulating type 2 immune responses.