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Upregulated PKM2 in Macrophages Exacerbates Experimental Arthritis via STAT1 Signaling

Jing Xu1, Congshan Jiang1, Xipeng Wang1

  • 1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, People's Republic of China; and Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an 710061, Shaanxi, People's Republic of China.

Journal of Immunology (Baltimore, Md. : 1950)
|June 7, 2020
PubMed

Insights

Pyruvate kinase M2 (Pkm2) is overexpressed in rheumatoid arthritis, promoting macrophage activation and inflammation. Inhibiting Pkm2 reduces arthritis severity and pro-inflammatory cytokine production, suggesting it as a potential therapeutic target.

Area of Science:

  • Biochemistry
  • Immunology
  • Rheumatology

Background:

  • Glucose metabolism is altered in rheumatoid arthritis (RA).
  • Pyruvate kinase M2 (Pkm2), a key glycolytic enzyme, is hypothesized to activate macrophages (Mφ) and drive RA inflammation.
  • Pkm2's role in RA pathogenesis requires elucidation.

Purpose of the Study:

  • To investigate the role of Pkm2 in macrophage activation and pro-inflammatory cytokine production in rheumatoid arthritis.
  • To determine if Pkm2 is a viable therapeutic target for RA treatment.

Main Methods:

  • Immunofluorescence, Western blotting, and qRT-PCR to detect Pkm2 expression in arthritic rat tissues.
  • Pharmacological inhibition of Pkm2 with shikonin and RNA interference (RNAi) in vivo and in vitro.
  • Assessment of arthritis severity, Mφ markers (ED1), and pro-inflammatory cytokines (Tnf-α, Il-1β) via Stat1 signaling pathway.

Main Results:

  • Pkm2 was significantly overexpressed in ED1-positive Mφ in arthritic rat spleens and synovial tissues.
  • Pkm2 inhibition or silencing alleviated arthritis severity, reduced Mφ markers, and decreased pro-inflammatory cytokine production.
  • Silencing Pkm2 in Mφ reduced Tnf-α and Il-1β production, mediated through Stat1 signaling.

Conclusions:

  • Pkm2 is highly expressed in Mφ in rheumatoid arthritis and promotes Mφ activation via Stat1 signaling.
  • Targeting Pkm2 may represent a promising therapeutic strategy for rheumatoid arthritis.

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