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SOCS1 is a negative regulator of metabolic reprogramming during sepsis
Annie Rocio Piñeros Alvarez, … , Jose Carlos Alves-Filho, C. Henrique Serezani
Annie Rocio Piñeros Alvarez, … , Jose Carlos Alves-Filho, C. Henrique Serezani
Published July 6, 2017
Citation Information: JCI Insight. 2017;2(13):e92530. https://doi.org/10.1172/jci.insight.92530.
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Research Article Immunology Metabolism

SOCS1 is a negative regulator of metabolic reprogramming during sepsis

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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.

Authors

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

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Figure 6

Increased glycolysis is responsible for iKIR-mediated animal mortality during sepsis.

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Increased glycolysis is responsible for iKIR-mediated animal mortality d...
Mice were treated with the competitive hexokinase inhibitor 2-deoxyglucose (2-DG; 0.5 g/kg, i.p.) daily for 4 days and 1 hour before cecal ligation and puncture (CLP). The animals were also treated with iKIR (inhibitor of the kinase inhibitory region), 24 hours and 1 hour before surgery. (A) Lactate levels in peritoneal exudate (n = 5–7 mice/group, 1-way ANOVA followed by Bonferroni correction). (B) Bacterial loads were determined in blood and peritoneal exudate 18 hours after CLP (n = 4–9 mice/group, 1-way ANOVA followed by Bonferroni correction). Levels of IL-1β (C) and TNF-α (D) were quantified in peritoneal exudate (n = 4–5 mice/group, 1-way ANOVA followed by Bonferroni correction). Scatter plot shows individual values, mean, and SEM. *P < 0.05, control-treated septic mice vs. naive; &P<0.05, iKIR vs. control-treated septic mice; %P<0.05, iKIR and 2-DG vs. iKIR-treated septic mice; #P<0.05, iKIR-septic mice vs. naive mice. PC, peritoneal cavity.
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