2. Academic Validation
  3. STAT3 S727 phosphorylation drives pathogenic Th17 differentiation and neuroinflammation in autoimmune disease

STAT3 S727 phosphorylation drives pathogenic Th17 differentiation and neuroinflammation in autoimmune disease

  • J Neuroinflammation. 2025 Oct 28;22(1):246. doi: 10.1186/s12974-025-03591-4.
Douglas S Prado # 1 2,  Achyudhan R Kutuva # 3 4 5 6,  Richard T Cattley 3 4,  Andreza Buzolin Sonego 3 4,  Parth Sutariya 3 4,  Elena Im 3 4,  Shuxian Wu 3,  Mijoon Lee 7,  Rachel L Cumberland 3 8,  Isha Mehta 3 4,  Greg M Delgoffe 3 8,  William C Boggess 7,  James R Faeder 5,  Mark J Shlomchik 3,  William F Hawse 9 10
Affiliations

Affiliations

  • 1 Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. PRADODDS@pitt.edu.
  • 2 Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA. PRADODDS@pitt.edu.
  • 3 Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 4 Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 5 Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 6 Joint Carnegie Mellon University, University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, PA, USA.
  • 7 Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
  • 8 Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
  • 9 Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. whawse@pitt.edu.
  • 10 Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA. whawse@pitt.edu.
  • # Contributed equally.
PMID: 41152886 DOI: 10.1186/s12974-025-03591-4
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.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12974-025-03591-4.

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