Impact Factor 6.429

The 5th most cited journal in Immunology

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2018.00419

Mitochondrial SIRT4 Resolves Immune Tolerance In Monocytes By Rebalancing Glycolysis And Glucose Oxidation Homeostasis

  • 1Scientific Research Center, Shanghai Public Health Clinical Center, China
  • 2Molecular Medicine Section, Department of Internal Medicine, Wake Forest School of Medicine, United States

The goal of this investigation was to define the molecular mechanism underlying physiologic conversion of immune tolerance to resolution of the acute inflammatory response, which is unknown. An example of this knowledge gap and its clinical importance is the broad-based energy deficit and immunometabolic paralysis reported in blood monocytes from non-survivors of human and mouse sepsis that precludes sepsis resolution. This immunometabolic dysregulation is biomarked by ex vivo endotoxin tolerance to increased glycolysis and TNF- expression. To investigate how tolerance switches to resolution, we adapted our previously documented models associated acute inflammatory, immune, and metabolic reprogramming that induces endotoxin tolerance as a model of sepsis in human monocytes We report here that mitochondrial sirtuin 4 (SIRT4) physiologically breaks tolerance and resolves acute inflammation in human monocytes by coordinately reprogramming metabolism and bioenergetics. We find that increased SIRT4 mRNA and protein expression during immune tolerance counters the increase in pyruvate dehydrogenase kinase 1 (PDK1) and SIRT1 that promote tolerance by switching glucose-dependent support of immune resistance to fatty acid oxidation support of immune tolerance. By decreasing SIRT4, PDC reactivation rebalances mitochondrial respiration and by decreasing SIRT1, SIRT4 increases fatty acid synthesis. The precise mechanism for the mitochondrial SIRT4 nuclear feedback is unclear, by our findings are consistent with a new concept in which mitochondrial SIRT4 directs the axis that controls anabolic and catabolic energy sources.

Keywords: monocyte, acute inflammation resolution, glucose metabolic homeostasis, SIRT4, Pyruvate Dehydrogenase Complex, Pyruvate Dehydrogenase Kinase

Received: 16 Dec 2017; Accepted: 15 Feb 2018.

Edited by:

Kai Fang, University of California, Los Angeles, United States

Reviewed by:

David Dombrowicz, Institut National de la Santé et de la Recherche Médicale (INSERM), France
Alessandra Durazzo, Consiglio per la ricerca in agricoltura e l'analisi dell'economia agraria (CREA), Italy  

Copyright: © 2018 Tao, Zhang, Ling, McCall and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Charles E. McCall, Wake Forest School of Medicine, Molecular Medicine Section, Department of Internal Medicine, Medical Center BLVD, Winston-Salem, 27157, NC, United States, chmccall@wakehealth.edu
Prof. Tie F. Liu, Shanghai Public Health Clinical Center, Scientific Research Center, Fudan University, Shanghai, 201508, China, liutiefu@shaphc.org