Journal article
STAT3 S727 phosphorylation drives pathogenic Th17 differentiation and neuroinflammation in autoimmune disease
Journal of neuroinflammation, v 22(1), 246
28 Oct 2025
PMID: 41152886
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
T helper 17 (Th17) cells are a heterogeneous subset of CD4⁺ T cells that mediate host defense and drive autoimmune pathology. While phosphorylation of STAT3 at tyrosine 705 (Y705) is essential for Th17 differentiation, the functional role of serine 727 (S727) phosphorylation remains unresolved. Here, we show that STAT3 S727 phosphorylation is selectively required for the differentiation and effector function of pathogenic Th17 (pTh17) cells. Mechanistically, S727 phosphorylation facilitates STAT3 interactions with transcriptional co-regulators and chromatin remodeling complexes, establishing a transcriptional and epigenetic landscape that reinforces pTh17 identity. A STAT3 S727A point mutation disrupts these interactions, resulting in aberrant STAT1 activation, elevated IFN-γ production, impaired glycolytic metabolism, and destabilization of the pTh17 program. Metabolomic and extracellular flux analyses revealed a marked reduction in glycolytic capacity and spare respiratory reserve in STAT3S727A Th17 cells, indicating that S727 phosphorylation is required for optimal bioenergetic fitness and effector programming. In vivo, CD4⁺ T cells expressing STAT3S727A have reduced pathological capacity in the experimental autoimmune encephalomyelitis (EAE), conferring protection in a murine model of multiple sclerosis. These findings uncover a noncanonical STAT3 signaling axis that integrates transcriptional and metabolic control of Th17-mediated neuroinflammation and suggest that selective targeting of S727 phosphorylation may offer therapeutic benefit in MS by disrupting both effector function and glycolytic support. One sentence summary. STAT3 S727 phosphorylation is essential for assembling transcriptional and metabolic programs that drive pathogenic Th17 differentiation and autoimmune neuroinflammation.
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Details
- Title
- STAT3 S727 phosphorylation drives pathogenic Th17 differentiation and neuroinflammation in autoimmune disease
- Creators
- Douglas S Prado (Corresponding Author) - University of PittsburghAchyudhan R Kutuva - University of PittsburghRichard T Cattley - University of PittsburghAndreza Buzolin Sonego - University of PittsburghParth J Sutariya - University of PittsburghElena Im - University of PittsburghShuxian Wu - University of PittsburghMijoon Lee - University of Notre DameRachel L Cumberland - University of PittsburghIsha Mehta - University of PittsburghGreg M Delgoffe - University of PittsburghWilliam C Boggess - University of Notre DameJames R Faeder - University of PittsburghMark Shlomchik - University of PittsburghWilliam F Hawse - University of Pittsburgh
- Publication Details
- Journal of neuroinflammation, v 22(1), 246
- Publisher
- Springer Nature
- Number of pages
- 18
- Grant note
- University of Pittsburgh Dean's Faculty Advancement Award Startup funds from the University of Pittsburgh National Institute of Health grant: 1R01AI175111
Library generation and sequencing were performed in the Health Sciences Sequencing Core at UPMC Children's Hospital of Pittsburgh, Rangos Research Center. Services and instruments used in this project were graciously supported, in part, by the University of Pittsburgh, the Office of the Senior Vice Chancellor for Health Sciences, the Department of Pediatrics, the Institute for Precision Medicine, and the Richard K Mellon Foundation for Pediatric Research. RRID: SCR_023116. We thank Jishnu Das for guidance on RNAseq data analysis and reviewing the manuscript.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine
- Web of Science ID
- WOS:001604752700001
- Other Identifier
- 991022202354304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Immunology
- Neurosciences