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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Communication

Markers of Type 2 Inflammation and Immunosenescence Are Upregulated in Localized Scleroderma

by
Lauren Khoury
1,
Connor Prosty
1,
Stephanie Ghazal
2,
Sofianne Gabrielli
1,
Kathryn S. Torok
3,
Mohammed Osman
4,
Elvis Martinez-Jaramillo
2,
Philippe Lefrançois
5 and
Elena Netchiporouk
2,*
1
Faculty of Medicine, McGill University, Montreal, QC H3G 2M1, Canada
2
Division Dermatology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
3
Department of Pediatrics (Rheumatology), University of Pittsburgh, Pittsburgh, PA 15224, USA
4
Division of Rheumatology, University of Alberta, Edmonton, AB T6G 2R3, Canada
5
Division Dermatology, Jewish General Hospital, Montreal, QC H3T 1E2, Canada
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(3), 1258; https://doi.org/10.3390/ijms26031258
Submission received: 5 December 2024 / Revised: 23 January 2025 / Accepted: 27 January 2025 / Published: 31 January 2025
(This article belongs to the Special Issue Scleroderma: From Biomarkers to Therapeutic Targets)
Versions Notes

Abstract

Localized scleroderma (LS) is an autoimmune, fibrotic skin disease that is thought to be triggered by environmental factors. Recent evidence from systemic autoimmune diseases proposed that the induction of immunosenescence may link environmental triggers with autoimmunity development. We aimed to explore the inflammatory signature in juvenile LS and investigate the presence of DNA instability and immunosenescence using publicly available transcriptomic data. High-throughput RNA sequencing data from 28 juvenile LS and 10 healthy controls were analyzed. Unsupervised clustering, pathway analyses, cell-type enrichment, fusion analyses, and immunosenescence gene set enrichment were performed. IFN and Type 1/2/3 pathways were upregulated in clinically active and histologically inflammatory LS. Type 2 inflammatory signature in both inflammatory and fibrotic LS was demonstrated by enriched genes, pathways, and deconvolution analyses (eosinophils). Features of genotoxic stress signals manifesting as DNA instability genes, pathways, and fusion events as well as mitochondrial dysfunction were demonstrated for the first time in LS. Features of immunosenescence (e.g., the upregulation of pathways involved in T cell exhaustion, inhibitory receptors, and cellular senescence and the enrichment of senescent genes) were also confirmed in (active and inflammatory) LS. Immunosenescence and inflammaging may underlie the complex and heterogeneous nature of immune responses seen in LS and should be further studied.
Keywords: immunology; inflammaging; morphea; pathogenesis; RNA sequencing; immunosenescence; autoimmunity; localized scleroderma immunology; inflammaging; morphea; pathogenesis; RNA sequencing; immunosenescence; autoimmunity; localized scleroderma

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MDPI and ACS Style

Khoury, L.; Prosty, C.; Ghazal, S.; Gabrielli, S.; Torok, K.S.; Osman, M.; Martinez-Jaramillo, E.; Lefrançois, P.; Netchiporouk, E. Markers of Type 2 Inflammation and Immunosenescence Are Upregulated in Localized Scleroderma. Int. J. Mol. Sci. 2025, 26, 1258. https://doi.org/10.3390/ijms26031258

AMA Style

Khoury L, Prosty C, Ghazal S, Gabrielli S, Torok KS, Osman M, Martinez-Jaramillo E, Lefrançois P, Netchiporouk E. Markers of Type 2 Inflammation and Immunosenescence Are Upregulated in Localized Scleroderma. International Journal of Molecular Sciences. 2025; 26(3):1258. https://doi.org/10.3390/ijms26031258

Chicago/Turabian Style

Khoury, Lauren, Connor Prosty, Stephanie Ghazal, Sofianne Gabrielli, Kathryn S. Torok, Mohammed Osman, Elvis Martinez-Jaramillo, Philippe Lefrançois, and Elena Netchiporouk. 2025. "Markers of Type 2 Inflammation and Immunosenescence Are Upregulated in Localized Scleroderma" International Journal of Molecular Sciences 26, no. 3: 1258. https://doi.org/10.3390/ijms26031258

APA Style

Khoury, L., Prosty, C., Ghazal, S., Gabrielli, S., Torok, K. S., Osman, M., Martinez-Jaramillo, E., Lefrançois, P., & Netchiporouk, E. (2025). Markers of Type 2 Inflammation and Immunosenescence Are Upregulated in Localized Scleroderma. International Journal of Molecular Sciences, 26(3), 1258. https://doi.org/10.3390/ijms26031258

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