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Single-cell transcriptomic profiling reveals functional heterogeneity and regulatory programs of neutrophils in experimental autoimmune uveitis.

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Τίτλος: Single-cell transcriptomic profiling reveals functional heterogeneity and regulatory programs of neutrophils in experimental autoimmune uveitis.
Συγγραφείς: Yang Z; Department of Ophthalmology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, PR China; Department of Optometry, North Sichuan Medical College, Nanchong, 637000, PR China., Xu L; Department of Ophthalmology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, PR China; Department of Optometry, North Sichuan Medical College, Nanchong, 637000, PR China. Electronic address: oculistxls@hotmail.com., Miao J; Department of Optometry, North Sichuan Medical College, Nanchong, 637000, PR China. Electronic address: miaojunming@nsmc.edu.cn.
Πηγή: Experimental eye research [Exp Eye Res] 2026 Oct; Vol. 271, pp. 111149. Date of Electronic Publication: 2026 Jul 01.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Academic Press Country of Publication: England NLM ID: 0370707 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0007 (Electronic) Linking ISSN: 00144835 NLM ISO Abbreviation: Exp Eye Res Subsets: MEDLINE
Imprint Name(s): Publication: London : Academic Press
Original Publication: London.
Ιατρικοί όροι (MeSH): Autoimmune Diseases*/genetics , Autoimmune Diseases*/immunology , Autoimmune Diseases*/metabolism , Neutrophils*/metabolism , Neutrophils*/immunology , Uveitis*/genetics , Uveitis*/immunology , Uveitis*/metabolism , Gene Expression Regulation*/physiology , Gene Expression Profiling* , Transcriptome*, Animals ; Mice ; Disease Models, Animal ; Mice, Inbred C57BL ; Single-Cell Gene Expression Analysis ; Female ; Single-Cell Analysis
Περίληψη: Background: Autoimmune uveitis (AU) is a vision-threatening ocular autoimmune disease. Previous studies have reported increased perivascular neutrophil infiltration during AU progression, yet the precise functional roles of these cells remain incompletely understood.
Methods: This study employed single-cell RNA sequencing (scRNA-seq) to systematically characterize neutrophils in the retina of experimental autoimmune uveitis (EAU) mice and to elucidate their regulatory mechanisms. scRNA-seq data were obtained from the mouse retinal samples of EAU and subjected to preprocessing, cell type annotation, neutrophil activation states analysis, differential gene expression analysis, functional enrichment, and transcription factor network inference, enabling a comprehensive exploration of neutrophil heterogeneity and functional features.
Results: EAU retinas exhibited markedly enhanced immune cell infiltration, with a significant increase in neutrophil proportion. Highly expressed neutrophil genes were enriched in transcription, translation, metabolism, and phagocytosis, and implicated key signaling pathways, including TNF, NF-κB, and MAPK, highlighting inflammatory responses as their principal function. Functional modules displayed a coordinated regulatory pattern. Neutrophils were further classified into two functionally distinct activation states: a dominant pro-inflammatory state (76.7%) and an anti-inflammatory/reparative state (23.3%), which differed significantly in gene expression, functional enrichment, and surface receptor profiles. Transcription factor network analysis identified upregulated factors such as Jun and downregulated factors such as Stat6, indicating their respective regulatory roles in pro-inflammatory and anti-inflammatory activation states. Several downstream target genes, including Arpp19 and Lyrm2, were co-regulated by multiple transcription factors.
Conclusion: This study reveals the heterogeneous features and regulatory networks of retinal neutrophils in EAU mice, clarifies differences between these neutrophil activation states, and identifies key regulatory molecules. These findings provide a theoretical foundation for understanding the pathogenesis of uveitis and for the development of precise therapeutic targets.
(Copyright © 2026 Elsevier Ltd. All rights reserved.)
Competing Interests: Declaration of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributed Indexing: Keywords: Autoimmune uveitis; Functional polarization; Immune heterogeneity; Neutrophils; Single-cell RNA sequencing
Entry Date(s): Date Created: 20260701 Date Completed: 20260831 Latest Revision: 20260831
Update Code: 20260901
DOI: 10.1016/j.exer.2026.111149
PMID: 42386026
Βάση Δεδομένων: MEDLINE
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  Data: Single-cell transcriptomic profiling reveals functional heterogeneity and regulatory programs of neutrophils in experimental autoimmune uveitis.
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  Data: <searchLink fieldCode="AU" term="%22Yang+Z%22">Yang Z</searchLink>; Department of Ophthalmology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, PR China; Department of Optometry, North Sichuan Medical College, Nanchong, 637000, PR China.<br /><searchLink fieldCode="AU" term="%22Xu+L%22">Xu L</searchLink>; Department of Ophthalmology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, PR China; Department of Optometry, North Sichuan Medical College, Nanchong, 637000, PR China. Electronic address: oculistxls@hotmail.com.<br /><searchLink fieldCode="AU" term="%22Miao+J%22">Miao J</searchLink>; Department of Optometry, North Sichuan Medical College, Nanchong, 637000, PR China. Electronic address: miaojunming@nsmc.edu.cn.
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  Data: <searchLink fieldCode="MM" term="%22Autoimmune+Diseases%22">Autoimmune Diseases*</searchLink>/<searchLink fieldCode="MM" term="%22Autoimmune+Diseases+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Autoimmune+Diseases%22">Autoimmune Diseases*</searchLink>/<searchLink fieldCode="MM" term="%22Autoimmune+Diseases+immunology%22">immunology</searchLink> <br /><searchLink fieldCode="MM" term="%22Autoimmune+Diseases%22">Autoimmune Diseases*</searchLink>/<searchLink fieldCode="MM" term="%22Autoimmune+Diseases+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Neutrophils%22">Neutrophils*</searchLink>/<searchLink fieldCode="MM" term="%22Neutrophils+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Neutrophils%22">Neutrophils*</searchLink>/<searchLink fieldCode="MM" term="%22Neutrophils+immunology%22">immunology</searchLink> <br /><searchLink fieldCode="MM" term="%22Uveitis%22">Uveitis*</searchLink>/<searchLink fieldCode="MM" term="%22Uveitis+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Uveitis%22">Uveitis*</searchLink>/<searchLink fieldCode="MM" term="%22Uveitis+immunology%22">immunology</searchLink> <br /><searchLink fieldCode="MM" term="%22Uveitis%22">Uveitis*</searchLink>/<searchLink fieldCode="MM" term="%22Uveitis+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Gene+Expression+Regulation%22">Gene Expression Regulation*</searchLink>/<searchLink fieldCode="MM" term="%22Gene+Expression+Regulation+physiology%22">physiology</searchLink> <br /><searchLink fieldCode="MM" term="%22Gene+Expression+Profiling%22">Gene Expression Profiling*</searchLink> <br /><searchLink fieldCode="MM" term="%22Transcriptome%22">Transcriptome*</searchLink><br /><searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%22">Mice</searchLink> ; <searchLink fieldCode="MH" term="%22Disease+Models%2C+Animal%22">Disease Models, Animal</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%2C+Inbred+C57BL%22">Mice, Inbred C57BL</searchLink> ; <searchLink fieldCode="MH" term="%22Single-Cell+Gene+Expression+Analysis%22">Single-Cell Gene Expression Analysis</searchLink> ; <searchLink fieldCode="MH" term="%22Female%22">Female</searchLink> ; <searchLink fieldCode="MH" term="%22Single-Cell+Analysis%22">Single-Cell Analysis</searchLink>
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  Data: Background: Autoimmune uveitis (AU) is a vision-threatening ocular autoimmune disease. Previous studies have reported increased perivascular neutrophil infiltration during AU progression, yet the precise functional roles of these cells remain incompletely understood.<br />Methods: This study employed single-cell RNA sequencing (scRNA-seq) to systematically characterize neutrophils in the retina of experimental autoimmune uveitis (EAU) mice and to elucidate their regulatory mechanisms. scRNA-seq data were obtained from the mouse retinal samples of EAU and subjected to preprocessing, cell type annotation, neutrophil activation states analysis, differential gene expression analysis, functional enrichment, and transcription factor network inference, enabling a comprehensive exploration of neutrophil heterogeneity and functional features.<br />Results: EAU retinas exhibited markedly enhanced immune cell infiltration, with a significant increase in neutrophil proportion. Highly expressed neutrophil genes were enriched in transcription, translation, metabolism, and phagocytosis, and implicated key signaling pathways, including TNF, NF-κB, and MAPK, highlighting inflammatory responses as their principal function. Functional modules displayed a coordinated regulatory pattern. Neutrophils were further classified into two functionally distinct activation states: a dominant pro-inflammatory state (76.7%) and an anti-inflammatory/reparative state (23.3%), which differed significantly in gene expression, functional enrichment, and surface receptor profiles. Transcription factor network analysis identified upregulated factors such as Jun and downregulated factors such as Stat6, indicating their respective regulatory roles in pro-inflammatory and anti-inflammatory activation states. Several downstream target genes, including Arpp19 and Lyrm2, were co-regulated by multiple transcription factors.<br />Conclusion: This study reveals the heterogeneous features and regulatory networks of retinal neutrophils in EAU mice, clarifies differences between these neutrophil activation states, and identifies key regulatory molecules. These findings provide a theoretical foundation for understanding the pathogenesis of uveitis and for the development of precise therapeutic targets.<br /> (Copyright © 2026 Elsevier Ltd. All rights reserved.)
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  Data: Declaration of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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