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<p>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<sup>+</sup> ILC2s and limited intestinal inflammation. Expression of genes encoding human ADM2 receptor (<i>CALCRL</i> and <i>RAMP3</i>) was altered in participants with inflammatory bowel diseases and associated with reduced expression of <i>AREG</i> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年8月15日

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  • Jazib Uddin,
  • Hiroshi Yano,
  • Christopher N. Parkhurst,
  • Wen Zhang,
  • Anees Ahmed,
  • Victoria Ribeiro de Godoy,
  • Qianru Wei,
  • Rohit Panchakshari,
  • Antoine Henninot,
  • Surya Dasgupta,
  • Stephen Gaudino,
  • Elizabeth R. Emanuel,
  • Peng Zeng,
  • Isabella Miranda,
  • Elin Hu,
  • Amy M. Tsou,
  • Randy Longman,
  • Gregory F. Sonnenberg,
  • Ellen Scherl,
  • Robbyn Sockolow,
  • Dana Lukin,
  • Vinita Jacob,
  • Laura Sahyoun,
  • Michael Mintz,
  • Lasha Gogokhia,
  • Thomas Ciecierega,
  • Aliza Solomon,
  • Arielle Bergman,
  • Kimberley Chein,
  • Elliott Gordon,
  • Lily Barash,
  • Michelle Ramos,
  • Kenny Joselin Castro Ochoa,
  • Adriana Brcic-Susak,
  • Dario Garone,
  • Lexi Tempera,
  • Chloe Scott,
  • Caitlin Mason,
  • David Artis

摘要

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.