Burns & trauma · 2026
A neutrophil-epithelial thrombospondin‑1-CD36-c‑Jun N‑terminal kinase axis orchestrates mucosal barrier failure in intestinal ischemia-reperfusion.
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Wang Yiwen, Li Ran, Zhuang Mengmeng, Fu Yuechen, Xu Qing, Qiao Luqi, Chen Simiao, Cao Jiayi, Li Kehui, Wang Ao, Meng Chao, Wang Wensheng, Sun Yong
Аннотация
BACKGROUND: Intestinal barrier failure following ischemia-reperfusion (IR) injury is a critical event that drives lethal systemic complications; however, the specific intercellular signals governing epithelial cell fate under these pathological conditions remain incompletely understood.
METHODS: We performed single-cell ribonucleic acid sequencing (scRNA-seq) on intestinal tissues from a murine IR model to map intercellular communication networks. The identified ligand-receptor pair was functionally validated using neutrophil-specific thrombospondin-1 (Thbs1) knockout mice, combined with pharmacological inhibition and activation of CD36, as well as biochemical and histological analyses.
RESULTS: scRNA-seq analysis of the IR-injured gut revealed a key neutrophil-epithelial signaling pathway mediated by the Thbs1-Cd36 ligand-receptor pair. Neutrophil-specific genetic ablation of Thbs1 markedly attenuated IR-induced epithelial apoptosis and barrier disruption. Mechanistically, THBS1 binding to epithelial CD36 activated JNK signaling, mediating a proapoptotic cascade. CD36 inhibition was protective, whereas its activation bypassed the requirement for THBS1 and provoked mucosal injury.
CONCLUSIONS: Our study elucidates a key mechanism of gut barrier failure and identifies the THBS1-CD36-JNK axis as a promising therapeutic target for mitigating intestinal IR injury in critical conditions such as burns and shock.
METHODS: We performed single-cell ribonucleic acid sequencing (scRNA-seq) on intestinal tissues from a murine IR model to map intercellular communication networks. The identified ligand-receptor pair was functionally validated using neutrophil-specific thrombospondin-1 (Thbs1) knockout mice, combined with pharmacological inhibition and activation of CD36, as well as biochemical and histological analyses.
RESULTS: scRNA-seq analysis of the IR-injured gut revealed a key neutrophil-epithelial signaling pathway mediated by the Thbs1-Cd36 ligand-receptor pair. Neutrophil-specific genetic ablation of Thbs1 markedly attenuated IR-induced epithelial apoptosis and barrier disruption. Mechanistically, THBS1 binding to epithelial CD36 activated JNK signaling, mediating a proapoptotic cascade. CD36 inhibition was protective, whereas its activation bypassed the requirement for THBS1 and provoked mucosal injury.
CONCLUSIONS: Our study elucidates a key mechanism of gut barrier failure and identifies the THBS1-CD36-JNK axis as a promising therapeutic target for mitigating intestinal IR injury in critical conditions such as burns and shock.