Pharmacological Inhibition of N-Acylethanolamine Acid Amidase (NAAA) Mitigates Intestinal Fibrosis Through Modulation of Macrophage Activity

  • J Crohns Colitis. 2025 Feb 4;19(2):jjae132. doi: 10.1093/ecco-jcc/jjae132.
Maria Francesca Nanì  1 ,  Ester Pagano  1 ,  Paola De Cicco  1 ,  Giuseppe Lucariello  1 ,  Fabio Cattaneo  2 ,  Francesca Paola Tropeano  3 ,  Donatella Cicia  1 ,  Rebecca Amico  1 ,  Federica Raucci  1 ,  Giuseppe Ercolano  1 ,  Francesco Maione  1 ,  Maria Michela Rinaldi  1 ,  Fabiana Esposito  1 ,  Rosario Ammendola  2 ,  Gaetano Luglio  3 ,  Raffaele Capasso  4 ,  Alexandros Makriyannis  5 ,  Stefania Petrosino  6  7 ,  Francesca Borrelli  1 ,  Barbara Romano  1 ,  Angelo A Izzo  1
Affiliations
  • 1. Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
  • 2. Department of Molecular Medicine and Medical Biotechnology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
  • 3. Department of Clinical Medicine and Surgery, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
  • 4. Department of Agricultural Sciences, University of Naples Federico II, Portici, Italy.
  • 5. Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
  • 6. Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy.
  • 7. Epitech Group SpA, Saccolongo, Italy.
PMID: 39211986 DOI: 10.1093/ecco-jcc/jjae132
Abstract

Background and aims: Intestinal fibrosis, a frequent complication of Inflammatory Bowel Disease, is characterized by stricture formation with no pharmacological treatment to date. N-acylethanolamine acid amidase (NAAA) is responsible for the hydrolysis of acylethanolamides (AEs, eg, palmitoylethanolamide and oleoylethanolamide). Here, we investigated NAAA and AE signaling in gut fibrosis.

Methods: NAAA and AE signaling were evaluated in human intestinal specimens from patients with stenotic Crohn's Disease (CD). Gut fibrosis was induced by 2,4,6-trinitrobenzenesulfonic acid, monitored by colonoscopy, and assessed by qRT-PCR, histological analyses, and confocal microscopy. Immune cells in mesenteric Lymph Nodes were analyzed by FACS. Colonic fibroblasts were cultured in conditioned media derived from polarized or non-polarized bone marrow-derived Macrophages (BMDMs). IL-23 signaling was evaluated by qRT-PCR, ELISA, FACS, and western blot in BMDMs and in lamina propria CX3CR1+ cells.

Results: In ileocolonic human CD strictures, increased transcript expression of NAAA was observed with a decrease in its substrates oleoylethanolamide and palmitoylethanolamide. NAAA inhibition reduced intestinal fibrosis in vivo, as indicated by a decrease in inflammatory parameters, Collagen deposition, and fibrosis-related genes, including those involved in epithelial-to-mesenchymal transition. More in-depth studies revealed modulation of the immune response related to IL-23 following NAAA inhibition. The antifibrotic actions of NAAA inhibition are mediated by Mφ and M2 Macrophages that indirectly affect fibroblast collagenogenesis. NAAA inhibitor AM9053 normalized IL-23 signaling in BMDMs and in lamina propria CX3CR1+ cells.

Conclusions: Our findings provide new insights into the pathophysiological mechanism of intestinal fibrosis and identify NAAA as a promising target for the development of therapeutic treatments to alleviate CD-related fibrosis.

Keywords
Acylethanolamides; IL-23; intestinal fibrosis.
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