SOCS1 is a negative regulator of metabolic reprogramming during sepsis

Annie Rocio Piñeros Alvarez, Nicole Glosson-Byers, Stephanie Brandt, Soujuan Wang, Hector Wong, Sarah Sturgeon, Brian Paul McCarthy, Paul Territo, Jose Carlos Alves-Filho, C. Henrique Serezani

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Sepsis can induce an overwhelming systemic inflammatory response, resulting in organ damage and death. Suppressor of cytokine signaling 1 (SOCS1) negatively regulates signaling by cytokine receptors and Toll-like receptors (TLRs). However, the cellular targets and molecular mechanisms for SOCS1 activity during polymicrobial sepsis are unknown. To address this, we utilized a cecal ligation and puncture (CLP) model for sepsis; C57BL/6 mice subjected to CLP were then treated with a peptide (iKIR) that binds the SOCS1 kinase inhibitory region (KIR) and blocks its activity. Treatment with iKIR increased CLP-induced mortality, bacterial burden, and inflammatory cytokine production. Myeloid cell-specific SOCS1 deletion (Socs1Δmyel) mice were also more susceptible to sepsis, demonstrating increased mortality, higher bacterial loads, and elevated inflammatory cytokines, compared with Socs1fl littermate controls. These effects were accompanied by macrophage metabolic reprograming, as evidenced by increased lactic acid production and elevated expression of the glycolytic enzymes hexokinase, lactate dehydrogenase A, and glucose transporter 1 in septic Socs1Δmyel mice. Upregulation was dependent on the STAT3/HIF-1α/glycolysis axis, and blocking glycolysis ameliorated increased susceptibility to sepsis in iKIR-treated CLP mice. These results reveal a role of SOCS1 as a regulator of metabolic reprograming that prevents overwhelming inflammatory response and organ damage during sepsis.

Original languageEnglish (US)
JournalJCI insight
Volume2
Issue number13
DOIs
StatePublished - Jul 6 2017

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Sepsis
Cytokines
Punctures
Ligation
Glycolysis
Cytokine Receptors
Hexokinase
Facilitative Glucose Transport Proteins
Mortality
Bacterial Load
Toll-Like Receptors
Myeloid Cells
Inbred C57BL Mouse
Lactic Acid
Phosphotransferases
Up-Regulation
Macrophages
Peptides
Enzymes

Keywords

  • Immunology
  • Metabolism

Cite this

Piñeros Alvarez, A. R., Glosson-Byers, N., Brandt, S., Wang, S., Wong, H., Sturgeon, S., ... Serezani, C. H. (2017). SOCS1 is a negative regulator of metabolic reprogramming during sepsis. JCI insight, 2(13). https://doi.org/10.1172/jci.insight.92530

SOCS1 is a negative regulator of metabolic reprogramming during sepsis. / Piñeros Alvarez, Annie Rocio; Glosson-Byers, Nicole; Brandt, Stephanie; Wang, Soujuan; Wong, Hector; Sturgeon, Sarah; McCarthy, Brian Paul; Territo, Paul; Alves-Filho, Jose Carlos; Serezani, C. Henrique.

In: JCI insight, Vol. 2, No. 13, 06.07.2017.

Research output: Contribution to journalArticle

Piñeros Alvarez, AR, Glosson-Byers, N, Brandt, S, Wang, S, Wong, H, Sturgeon, S, McCarthy, BP, Territo, P, Alves-Filho, JC & Serezani, CH 2017, 'SOCS1 is a negative regulator of metabolic reprogramming during sepsis', JCI insight, vol. 2, no. 13. https://doi.org/10.1172/jci.insight.92530
Piñeros Alvarez AR, Glosson-Byers N, Brandt S, Wang S, Wong H, Sturgeon S et al. SOCS1 is a negative regulator of metabolic reprogramming during sepsis. JCI insight. 2017 Jul 6;2(13). https://doi.org/10.1172/jci.insight.92530
Piñeros Alvarez, Annie Rocio ; Glosson-Byers, Nicole ; Brandt, Stephanie ; Wang, Soujuan ; Wong, Hector ; Sturgeon, Sarah ; McCarthy, Brian Paul ; Territo, Paul ; Alves-Filho, Jose Carlos ; Serezani, C. Henrique. / SOCS1 is a negative regulator of metabolic reprogramming during sepsis. In: JCI insight. 2017 ; Vol. 2, No. 13.
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