Ni Xie, Guanhao Su, Ying Wu, Kui Peng, Zhu Mei, Wei Chen, Kai Xu, Baiwen Li
{"title":"Muscularis EGR1 Deficiency Impairs M2 Macrophage Polarization and Disrupts Gastric Motility in Diabetic Gastroparesis.","authors":"Ni Xie, Guanhao Su, Ying Wu, Kui Peng, Zhu Mei, Wei Chen, Kai Xu, Baiwen Li","doi":"10.1111/nmo.70439","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Diabetic gastroparesis (DGP) is characterized by delayed gastric emptying and limited mechanism-based therapies. Pyloric dysfunction has been associated with loss of interstitial cells of Cajal (ICC) and altered muscularis macrophage polarization. This study examined whether early growth response 1 (EGR1) links macrophage polarization to ICC integrity in DGP.</p><p><strong>Methods: </strong>Human full-thickness gastric body transcriptomic data (GSE115601) were analyzed using differential expression and exploratory machine learning, with validation in single-cell RNA sequencing data (GSE252126) and clinical pyloric muscularis biopsies. A streptozotocin-induced DGP rat model was used to test local pyloric adeno-associated virus 9 (AAV9)-mediated EGR1 restoration. Macrophage and primary ICC experiments included EGR1 knockdown, thioredoxin 2 (TXN2) rescue, mitochondrial respiration analysis, cytokine profiling, C-C motif chemokine ligand 5 (CCL5) neutralization, and C-C chemokine receptor 5 (CCR5) blockade.</p><p><strong>Results: </strong>EGR1 was downregulated in DGP gastric body samples and subsequently validated in human pyloric muscularis biopsies, with enrichment in macrophages, particularly M2 macrophages. EGR1 loss reduced TXN2 transcription and mitochondrial oxidative phosphorylation (OXPHOS), impaired M2 polarization, and increased macrophage CCL5 secretion. Conditioned medium from EGR1-deficient macrophages induced Ca<sup>2+</sup> dysregulation, NLR family pyrin domain containing 3 (NLRP3) activation, and ICC marker loss; these effects were attenuated by CCL5 neutralization or CCR5 blockade. Local AAV9-EGR1 restoration increased M2 macrophage and ICC marker expression, improved gastric emptying, and regularized pyloric slow waves without improving systemic glucose control.</p><p><strong>Conclusions: </strong>Muscularis EGR1 deficiency may promote DGP by disrupting TXN2-dependent macrophage OXPHOS and triggering CCL5/CCR5/NLRP3-mediated ICC injury. Local EGR1 restoration improved gastric motility and may represent a therapeutic strategy.</p>","PeriodicalId":19123,"journal":{"name":"Neurogastroenterology and Motility","volume":"38 9","pages":"e70439"},"PeriodicalIF":3.0000,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13578571/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurogastroenterology and Motility","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/nmo.70439","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Diabetic gastroparesis (DGP) is characterized by delayed gastric emptying and limited mechanism-based therapies. Pyloric dysfunction has been associated with loss of interstitial cells of Cajal (ICC) and altered muscularis macrophage polarization. This study examined whether early growth response 1 (EGR1) links macrophage polarization to ICC integrity in DGP.
Methods: Human full-thickness gastric body transcriptomic data (GSE115601) were analyzed using differential expression and exploratory machine learning, with validation in single-cell RNA sequencing data (GSE252126) and clinical pyloric muscularis biopsies. A streptozotocin-induced DGP rat model was used to test local pyloric adeno-associated virus 9 (AAV9)-mediated EGR1 restoration. Macrophage and primary ICC experiments included EGR1 knockdown, thioredoxin 2 (TXN2) rescue, mitochondrial respiration analysis, cytokine profiling, C-C motif chemokine ligand 5 (CCL5) neutralization, and C-C chemokine receptor 5 (CCR5) blockade.
Results: EGR1 was downregulated in DGP gastric body samples and subsequently validated in human pyloric muscularis biopsies, with enrichment in macrophages, particularly M2 macrophages. EGR1 loss reduced TXN2 transcription and mitochondrial oxidative phosphorylation (OXPHOS), impaired M2 polarization, and increased macrophage CCL5 secretion. Conditioned medium from EGR1-deficient macrophages induced Ca2+ dysregulation, NLR family pyrin domain containing 3 (NLRP3) activation, and ICC marker loss; these effects were attenuated by CCL5 neutralization or CCR5 blockade. Local AAV9-EGR1 restoration increased M2 macrophage and ICC marker expression, improved gastric emptying, and regularized pyloric slow waves without improving systemic glucose control.
Conclusions: Muscularis EGR1 deficiency may promote DGP by disrupting TXN2-dependent macrophage OXPHOS and triggering CCL5/CCR5/NLRP3-mediated ICC injury. Local EGR1 restoration improved gastric motility and may represent a therapeutic strategy.
期刊介绍：
Neurogastroenterology & Motility (NMO) is the official Journal of the European Society of Neurogastroenterology & Motility (ESNM) and the American Neurogastroenterology and Motility Society (ANMS). It is edited by James Galligan, Albert Bredenoord, and Stephen Vanner. The editorial and peer review process is independent of the societies affiliated to the journal and publisher: Neither the ANMS, the ESNM or the Publisher have editorial decision-making power. Whenever these are relevant to the content being considered or published, the editors, journal management committee and editorial board declare their interests and affiliations.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
