PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation
| Autor: | Marcos Henrique Rosa, Miriam M. Fonseca, Juliana E Toller-Kawahisa, Fernando Silva Ramalho, Douglas Silva Prado, Gabriel Azevedo Publio, Timna Varela Martins, Luis Eduardo Alves Damasceno, Flávio P. Veras, Thiago M. Cunha, Ari Waisman, José C. Alves-Filho, Fernando Q. Cunha |
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| Rok vydání: | 2020 |
| Předmět: |
STAT3 Transcription Factor
0301 basic medicine Encephalomyelitis Autoimmune Experimental Cellular differentiation Encephalomyelitis Pyruvate Kinase Immunology Fluorescent Antibody Technique Autoimmunity Inflammation PKM2 Real-Time Polymerase Chain Reaction Article Mice 03 medical and health sciences 0302 clinical medicine Neuroinflammation medicine Animals Immunology and Allergy STAT3 biology Chemistry Experimental autoimmune encephalomyelitis Cell Differentiation hemic and immune systems Flow Cytometry medicine.disease Cell biology Mice Inbred C57BL 030104 developmental biology Tumor progression 030220 oncology & carcinogenesis biology.protein Th17 Cells medicine.symptom REAÇÃO EM CADEIA POR POLIMERASE Pyruvate kinase |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Th17 cells undergo metabolic reprogramming towards glycolysis to support their differentiation and pathogenicity. Damasceno et al. report that PKM2, a glycolytic enzyme, plays a nonmetabolic role in mediating Th17 cell differentiation and autoimmune neuroinflammation by fine-tuning STAT3 activation. Th17 cell differentiation and pathogenicity depend on metabolic reprogramming inducing shifts toward glycolysis. Here, we show that the pyruvate kinase M2 (PKM2), a glycolytic enzyme required for cancer cell proliferation and tumor progression, is a key factor mediating Th17 cell differentiation and autoimmune inflammation. We found that PKM2 is highly expressed throughout the differentiation of Th17 cells in vitro and during experimental autoimmune encephalomyelitis (EAE) development. Strikingly, PKM2 is not required for the metabolic reprogramming and proliferative capacity of Th17 cells. However, T cell–specific PKM2 deletion impairs Th17 cell differentiation and ameliorates symptoms of EAE by decreasing Th17 cell–mediated inflammation and demyelination. Mechanistically, PKM2 translocates into the nucleus and interacts with STAT3, enhancing its activation and thereby increasing Th17 cell differentiation. Thus, PKM2 acts as a critical nonmetabolic regulator that fine-tunes Th17 cell differentiation and function in autoimmune-mediated inflammation. |
| Databáze: | OpenAIRE |
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