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. 2025 Sep;26(9):1516-1526.
doi: 10.1038/s41590-025-02243-2. Epub 2025 Aug 15.

CGRP-related neuropeptide adrenomedullin 2 promotes tissue-protective ILC2 responses and limits intestinal inflammation

Jazib Uddin  1   2   3   4   5 , Hiroshi Yano  1   2   3   4   5 , Christopher N Parkhurst  1   2   3   4   5 , Wen Zhang  1   2   3   4   5 , Anees Ahmed  1   2   3   4   5 , Victoria Ribeiro de Godoy  1   2   3   4   5 , Qianru Wei  1   2   3   4   5 , Rohit Panchakshari  6 , Antoine Henninot  6 , Surya Dasgupta  6 , Stephen Gaudino  1   2   3   4   5 , Elizabeth R Emanuel  1   2   3   4   5 , Peng Zeng  1   2   3   4   5 , Isabella Miranda  1   2   3   4   5 , Elin Hu  1   2   3   4   5 , Amy M Tsou  1   2   3   4   5 ; JRI Live Cell Bank; David Artis  7   8   9   10   11
Collaborators, Affiliations

CGRP-related neuropeptide adrenomedullin 2 promotes tissue-protective ILC2 responses and limits intestinal inflammation

Jazib Uddin et al. Nat Immunol. 2025 Sep.

Abstract

Neuro-immune circuits regulate innate and adaptive immunity at barrier surfaces. However, the differential impact of these circuits on proinflammatory versus tissue-protective responses remains poorly defined. We demonstrate that enteric neurons produce calcitonin gene-related peptide-related adrenomedullin 2 (ADM2) and identify a previously unrecognized role for the ADM2 pathway in promoting intestinal tissue-protective functions of group 2 innate lymphoid cells (ILC2s). Genomic or ILC2-intrinsic deletion of ADM2 receptor subunits resulted in a significant reduction in tissue-protective ILC2 responses, defective amphiregulin (AREG) production and increased susceptibility to intestinal damage and inflammation. Conversely, therapeutic delivery of recombinant ADM2 elicited tissue-protective AREG+ ILC2s and limited intestinal inflammation. Expression of genes encoding human ADM2 receptor (CALCRL and RAMP3) was altered in participants with inflammatory bowel diseases and associated with reduced expression of AREG in ILC2s. Collectively, these findings identify that the ADM2-ADM2 receptor pathway can promote tissue-protective functions of ILC2s in the context of intestinal damage and inflammation.

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Conflict of interest statement

Competing interests: D.A. has contributed to scientific advisory boards at Pfizer, Takeda and the KRF. The other authors declare no competing interests.

References

    1. Klein Wolterink, R. G. J., Wu, G. S., Chiu, I. M. & Veiga-Fernandes, H. Neuroimmune interactions in peripheral organs. Annu. Rev. Neurosci. 45, 339–360 (2022). - PubMed
    1. Klose, C. S. & Artis, D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat. Immunol. 17, 765–774 (2016). - PubMed
    1. Colonna, M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Immunity 48, 1104–1117 (2018). - PubMed - PMC
    1. Ebbo, M., Crinier, A., Vély, F. & Vivier, E. Innate lymphoid cells: major players in inflammatory diseases. Nat. Rev. Immunol. 17, 665–678 (2017). - PubMed
    1. Salvador, A. F., de Lima, K. A. & Kipnis, J. Neuromodulation by the immune system: a focus on cytokines. Nat. Rev. Immunol. 21, 526–541 (2021). - PubMed

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