Academic Journal
Targeting soluble PD-1 alleviates peritoneal fibrosis by modulating PD-L1 recycling and mesothelial-mesenchymal transition.
| Τίτλος: | Targeting soluble PD-1 alleviates peritoneal fibrosis by modulating PD-L1 recycling and mesothelial-mesenchymal transition. |
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| Συγγραφείς: | Peng H; Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, No.127, Changle West Road, Xi'an, 710032, China., Feng S; Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, No.127, Changle West Road, Xi'an, 710032, China., Xiao K; Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, No.127, Changle West Road, Xi'an, 710032, China; Grade 2021 Clinical Medicine (Five-Year Program), Basic Medical College, The Fourth Military Medical University, Xi'an, China., Li J; Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, No.127, Changle West Road, Xi'an, 710032, China., Xu X; Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, No.127, Changle West Road, Xi'an, 710032, China., Wu M; Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, No.127, Changle West Road, Xi'an, 710032, China., Zhao F; Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, No.127, Changle West Road, Xi'an, 710032, China., Zha Y; Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, No.127, Changle West Road, Xi'an, 710032, China., Lu R; Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, No.127, Changle West Road, Xi'an, 710032, China., Chen Y; Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, No.127, Changle West Road, Xi'an, 710032, China., Yang G; Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, China. Electronic address: yanggd@fmmu.edu.cn., Zhao Y; Department of Medical Microbiology and parasitology, The Fourth Military Medical University, Xi'an, China. Electronic address: zhaoya@fmmu.edu.cn., Zhang Y; Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, No.127, Changle West Road, Xi'an, 710032, China. Electronic address: zhangyuting_51@163.com., He L; Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, No.127, Changle West Road, Xi'an, 710032, China. Electronic address: helijie@fmmu.edu.cn. |
| Πηγή: | Translational research : the journal of laboratory and clinical medicine [Transl Res] 2026 Oct; Vol. 296, pp. 70-82. Date of Electronic Publication: 2026 Jul 14. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Country of Publication: United States NLM ID: 101280339 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-1810 (Electronic) Linking ISSN: 18781810 NLM ISO Abbreviation: Transl Res Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: New York, N.Y. : Elsevier, [2006]- |
| Ιατρικοί όροι (MeSH): | Peritoneal Fibrosis*/pathology , Peritoneal Fibrosis*/metabolism , Peritoneal Fibrosis*/blood , B7-H1 Antigen*/metabolism , Programmed Cell Death 1 Receptor*/blood , Programmed Cell Death 1 Receptor*/metabolism , Epithelial-Mesenchymal Transition*, Exosomes/metabolism ; Animals ; Humans ; Mice ; Male ; Mice, Inbred C57BL ; Peritoneal Dialysis ; Female |
| Περίληψη: | Background: Peritoneal fibrosis (PF) is a major cause of technique failure in long-term peritoneal dialysis (PD) patients, driven by a chronic microinflammatory state. While T-cell activation is implicated, the role of soluble programmed death-1 (sPD-1), primarily derived from activated T cells, in PF pathogenesis remains elusive. Methods: We initially analyzed serum sPD-1 levels in PD patients and employed a mice PF model induced by high-glucose dialysate and lipopolysaccharide (LPS). The functional impact of sPD-1 on the progression of PF was assessed through the administration of a PD-L1 fusion protein, or engineered exosomes designed to adsorb sPD-1. Results: Serum sPD-1 levels were significantly elevated in long-term PD patients and were positively correlated with dialysis duration and markers of fibrosis, but inversely correlating with peritoneal function. In mice, exogenous sPD-1 exacerbated PF, whereas blockade with a PD-L1 fusion protein or sPD-1-adsorbing engineered exosomes markedly attenuated fibrosis, reduced T-cell infiltration, and preserved peritoneal function. Mechanistically, sPD-1 bound to PD-L1 on PMCs, triggering clathrin-mediated endocytosis. This interaction diverted PD-L1 from the lysosomal degradation pathway towards the Rab11-positive recycling endosome pathway, resulting in sustained upregulation of surface PD-L1 expression. This aberrant PD-L1 recycling activated pro-fibrotic signaling, culminating in mesothelial-to-mesenchymal transition (MMT). Conclusion: sPD-1 is a pivotal mediator linking peritoneal microinflammation to fibrosis by modulating the endocytic fate of PD-L1 in mesothelial cells. Targeting sPD-1, particularly using engineered exosomes or a PD-L1 fusion protein, represents a promising therapeutic strategy for preventing and treating peritoneal fibrosis. (Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Contributed Indexing: | Keywords: Endosomes; Mesothelial-mesenchymal transition; Peritoneal dialysis; Peritoneal fibrosis; Targeted therapy; sPD-1 |
| Substance Nomenclature: | 0 (B7-H1 Antigen) 0 (Programmed Cell Death 1 Receptor) 0 (CD274 protein, human) |
| Entry Date(s): | Date Created: 20260714 Date Completed: 20260829 Latest Revision: 20260829 |
| Update Code: | 20260830 |
| DOI: | 10.1016/j.trsl.2026.07.005 |
| PMID: | 42448218 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1878-1810 |
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| DOI: | 10.1016/j.trsl.2026.07.005 |