N-酰基乙醇胺酸酰胺酶（NAAA）的药理学抑制通过调节巨噬细胞活性减轻肠道纤维化。

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

作者信息

Nanì Maria Francesca, Pagano Ester, De Cicco Paola, Lucariello Giuseppe, Cattaneo Fabio, Tropeano Francesca Paola, Cicia Donatella, Amico Rebecca, Raucci Federica, Ercolano Giuseppe, Maione Francesco, Rinaldi Maria Michela, Esposito Fabiana, Ammendola Rosario, Luglio Gaetano, Capasso Raffaele, Makriyannis Alexandros, Petrosino Stefania, Borrelli Francesca, Romano Barbara, Izzo Angelo A

机构信息

Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.

Department of Molecular Medicine and Medical Biotechnology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.

出版信息

J Crohns Colitis. 2025 Feb 4;19(2). doi: 10.1093/ecco-jcc/jjae132.

DOI:10.1093/ecco-jcc/jjae132

PMID:39211986

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11836880/

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.

摘要

背景与目的

肠道纤维化是炎症性肠病的常见并发症，其特征为形成狭窄，迄今为止尚无药物治疗方法。N-酰基乙醇胺酸酰胺酶（NAAA）负责酰基乙醇胺（AEs，如棕榈酰乙醇胺和油酰乙醇胺）的水解。在此，我们研究了肠道纤维化中的NAAA和AE信号通路。

方法

在患有狭窄性克罗恩病（CD）患者的人体肠道标本中评估NAAA和AE信号通路。通过2,4,6-三硝基苯磺酸诱导肠道纤维化，通过结肠镜检查进行监测，并通过qRT-PCR、组织学分析和共聚焦显微镜进行评估。通过流式细胞术分析肠系膜淋巴结中的免疫细胞。在源自极化或非极化骨髓来源巨噬细胞（BMDM）的条件培养基中培养结肠成纤维细胞。通过qRT-PCR、ELISA、流式细胞术和蛋白质印迹法在BMDM和固有层CX3CR1+细胞中评估IL-23信号通路。

结果

在回结肠型人类CD狭窄中，观察到NAAA的转录表达增加，而其底物油酰乙醇胺和棕榈酰乙醇胺减少。NAAA抑制可减轻体内肠道纤维化，表现为炎症参数、胶原蛋白沉积和纤维化相关基因（包括参与上皮-间质转化的基因）减少。更深入的研究表明，NAAA抑制后与IL-23相关的免疫反应受到调节。NAAA抑制的抗纤维化作用由Mφ和M2巨噬细胞介导，它们间接影响成纤维细胞胶原蛋白生成。NAAA抑制剂AM9053使BMDM和固有层CX3CR1+细胞中的IL-23信号通路恢复正常。