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<p>Although the extracellular matrix (ECM) is a highly dynamic partner of the immune system, its immunoregulatory role during the early phase of sepsis-induced acute lung injury (ALI) remains poorly defined. Using a murine cecal ligation and puncture (CLP) model, we observed dynamic ECM remodeling characterized by rapid collagen loss within 24 h, followed by a pathological fibroproliferation phase. Proteomic profiling of the degraded ECM demonstrated its immunoregulatory potential. <i>In vitro</i> studies revealed that annexin A1 (ANXA1), an upregulated ECM component, promoted anti-inflammatory macrophage polarization via the formyl-peptide receptor 2/lipoxin A4 (FPR2/ALX)-dependent 5′-adenosine monophosphate-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway. However, under pathological conditions, collagen loss markedly reduces the number of key binding sites for integrin β1 (Itgb1), thereby disrupting macrophage-ECM adhesion and resulting in macrophage detachment; upon entering the inflammatory microenvironment, these cells acquire a proinflammatory phenotype, exacerbating pulmonary inflammation. Capitalizing on the collagen biosynthetic function of ascorbic acid (AA), we investigated its capacity to restore macrophage-ECM adhesion therapeutically. <i>In vitro</i>, treatment of fibroblasts with AA on decellularized CLP-ECM increased collagen deposition and improved macrophage adhesion. <i>In vivo</i>, intratracheal instillation of AA (20 mg/kg) enhanced collagen biosynthesis, which promoted ECM restoration, sustained interstitial macrophage retention, suppressed proinflammatory cytokine production, and ultimately resolved lung injury. Our study reveals that ECM degradation is an early immunoregulatory event and suggests a therapeutic approach for ECM repair via airway-targeted AA delivery in ALI.</p>

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The janus-faced extracellular matrix remodeling in acute lung injury: a gatekeeper of macrophage localization and phenotype

  • 期刊论文

  • 发表日期：

    2026年5月22日

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  • Feiyan Xie,
  • Yuheng Sun,
  • Xinyan Wei,
  • Wei Zhang,
  • Wei Luo,
  • Jie Huang,
  • Shencun Fang,
  • Xinxin Zhang,
  • Haibo Qiu,
  • Jie Chao

摘要

Although the extracellular matrix (ECM) is a highly dynamic partner of the immune system, its immunoregulatory role during the early phase of sepsis-induced acute lung injury (ALI) remains poorly defined. Using a murine cecal ligation and puncture (CLP) model, we observed dynamic ECM remodeling characterized by rapid collagen loss within 24 h, followed by a pathological fibroproliferation phase. Proteomic profiling of the degraded ECM demonstrated its immunoregulatory potential. In vitro studies revealed that annexin A1 (ANXA1), an upregulated ECM component, promoted anti-inflammatory macrophage polarization via the formyl-peptide receptor 2/lipoxin A4 (FPR2/ALX)-dependent 5′-adenosine monophosphate-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway. However, under pathological conditions, collagen loss markedly reduces the number of key binding sites for integrin β1 (Itgb1), thereby disrupting macrophage-ECM adhesion and resulting in macrophage detachment; upon entering the inflammatory microenvironment, these cells acquire a proinflammatory phenotype, exacerbating pulmonary inflammation. Capitalizing on the collagen biosynthetic function of ascorbic acid (AA), we investigated its capacity to restore macrophage-ECM adhesion therapeutically. In vitro, treatment of fibroblasts with AA on decellularized CLP-ECM increased collagen deposition and improved macrophage adhesion. In vivo, intratracheal instillation of AA (20 mg/kg) enhanced collagen biosynthesis, which promoted ECM restoration, sustained interstitial macrophage retention, suppressed proinflammatory cytokine production, and ultimately resolved lung injury. Our study reveals that ECM degradation is an early immunoregulatory event and suggests a therapeutic approach for ECM repair via airway-targeted AA delivery in ALI.