| Autor: |
Piñeros Alvarez AR; Department Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.; Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil., Glosson-Byers N; Department Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.; Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Brandt S; Department Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.; Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Wang S; Department Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.; Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Wong H; Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA., Sturgeon S; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., McCarthy BP; Center for In Vivo Imaging, Department Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA., Territo PR; Center for In Vivo Imaging, Department Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA., Alves-Filho JC; Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.; Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil., Serezani CH; Department Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.; Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. |
| Abstrakt: |
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. |
