Tetramerization of STAT5 promotes autoimmune-mediated neuroinflammation

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Abstract
Signal tranducer and activator of transcription 5 (STAT5) plays a critical role in mediating cellular responses following cytokine stimulation. STAT proteins critically signal via the formation of dimers, but additionally, STAT tetramers serve key biological roles, and we previously reported their importance in T and natural killer (NK) cell biology. However, the role of STAT5 tetramerization in autoimmune-mediated neuroinflammation has not been investigated. Using the STAT5 tetramer-deficient Stat5a-Stat5b N-domain double knockin (DKI) mouse strain, we report here that STAT5 tetramers promote the pathogenesis of experimental autoimmune encephalomyelitis (EAE). The mild EAE phenotype observed in DKI mice correlates with the impaired extravasation of pathogenic T-helper 17 (Th17) cells and interactions between Th17 cells and monocyte-derived cells (MDCs) in the meninges. We further demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF)–mediated STAT5 tetramerization regulates the production of CCL17 by MDCs. Importantly, CCL17 can partially restore the pathogenicity of DKI Th17 cells, and this is dependent on the activity of the integrin VLA-4. Thus, our study reveals a GM-CSF-STAT5 tetramer-CCL17 pathway in MDCs that promotes autoimmune neuroinflammation. Significance Multiple sclerosis (MS) is an immune-mediated disease that impacts the central nervous system. A murine model of MS, experimental autoimmune encephalomyelitis (EAE), is used to determine the mechanism of MS pathogenesis. STAT5 is a transcription factor that plays a critical role in mediating cellular responses following cytokine stimulation. Activated STAT5 proteins undergo functional dimerization and tetramerization. This study demonstrates that STAT5 tetramers promote the pathogenesis of EAE. STAT5 tetramers facilitate the interactions between Th17 cells and monocyte-derived cells (MDCs) in the meninges. In addition, the STAT5 tetramer-mediated expression of the chemokine CCL17 in MDCs promotes Th17 cell extravasation in the meninges. Thus, our study identified a GM-CSF-STAT5 tetramer-CCL17 pathway that can be therapeutically targeted.
Funding Information
  • HHS | National Institutes of Health (P20 GM109098)
  • HHS | National Institutes of Health (P20 GM103434)
  • HHS | National Institutes of Health (U54 GM104942)
  • Praespero Innovation Award Program (N/A)

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