TY - JOUR AU - Piñeros Alvarez, Annie Rocio AU - Glosson-Byers, Nicole AU - Brandt, Stephanie AU - Wang, Soujuan AU - Wong, Hector AU - Sturgeon, Sarah AU - McCarthy, Brian Paul AU - Territo, Paul R. AU - Alves-Filho, Jose Carlos AU - Serezani, C. Henrique T1 - SOCS1 is a negative regulator of metabolic reprogramming during sepsis PY - 2017/07/06/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.92530 VL - 2 IS - 13 UR - https://doi.org/10.1172/jci.insight.92530 PB - The American Society for Clinical Investigation ER -