PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation

Author(s):Show less -

Alves Damasceno, Luis Eduardo ^{[1, 2]} ; Prado, Douglas Silva ^{[1, 2]} ; Veras, Flavio Protasio ^{[1, 2]} ; Fonseca, Miriam M. ^{[1, 2]} ; Toller-Kawahisa, Juliana E. ^{[1, 2]} ; Rosa, Marcos Henrique ^{[1, 2]} ; Publio, Gabriel Azevedo ^{[1, 2]} ; Martins, Timna Varela ^{[1, 2]} ; Ramalho, Fernando S. ^[3] ; Waisman, Ari ^[4] ; Cunha, Fernando Queiroz ^{[1, 2]} ; Cunha, Thiago Mattar ^{[1, 2]} ; Alves-Filho, Jose Carlos ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Ctr Res Inflammatory Dis, Ribeirao Preto Med Sch, Ribeirao Preto - Brazil

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pathol, Ribeirao Preto - Brazil

^[4] Johannes Gutenberg Univ Mainz, Inst Mol Med, Univ Med Ctr, Mainz - Germany

• Document type: Journal article
• Source: JOURNAL OF EXPERIMENTAL MEDICINE; v. 217, n. 10 OCT 2020.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 16/05377-3 - Role of Erk5 pathway on Th17 and Treg cells differentiation and on experimental autoimmune encephalomyelitis
• Grantee: Douglas da Silva Prado
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/01714-8 - PKM2 contribution to neutrophils' activation in experimental systemic lupus erythematosus onset
• Grantee: Juliana Escher Toller
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/23910-6 - Role of PFKFB-3 enzyme in regulatory t cells
• Grantee: Marcos Henrique Rosa
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 16/10280-9 - Involvement of the enzyme pyruvate kinase M2 (PKM2) in the differentiation of Th17 lymphocytes and pathogenesis of experimental autoimmune encephalomyelitis
• Grantee: Luis Eduardo Alves Damasceno
• Support Opportunities: Scholarships in Brazil - Master