Journal ArticleDOI
Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis
Shih-Chin Cheng,Brendon P. Scicluna,Rob J.W. Arts,Mark S. Gresnigt,Ekta Lachmandas,Evangelos J. Giamarellos-Bourboulis,Matthijs Kox,Ganesh R. Manjeri,Ganesh R. Manjeri,Jori A. L. Wagenaars,Olaf L. Cremer,Jenneke Leentjens,Anne Jan van der Meer,Frank L. van de Veerdonk,Marc J. M. Bonten,Marcus J. Schultz,Peter H.G.M. Willems,Peter Pickkers,Leo A. B. Joosten,Tom van der Poll,Mihai G. Netea +20 more
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TLDR
The transcriptional and metabolic profiling of human patients with sepsis found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense, and the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-γ, which suggested that metabolic processes might represent a therapeutic target in sepsi.Abstract:
The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-γ, which suggested that metabolic processes might represent a therapeutic target in sepsis.read more
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Journal ArticleDOI
The immunopathology of sepsis and potential therapeutic targets
TL;DR: Pivotal for the clinical development of new sepsis therapies is the selection of patients on the basis of biomarkers and/or functional defects that provide specific insights into the expression or activity of the therapeutic target.
Journal ArticleDOI
BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity
Rob J.W. Arts,Simone J.C.F.M. Moorlag,Boris Novakovic,Yang Li,Shuang-Yin Wang,Marije Oosting,Vinod Kumar,Ramnik J. Xavier,Cisca Wijmenga,Leo A. B. Joosten,Chantal B.E.M. Reusken,Christine Stabell Benn,Christine Stabell Benn,Peter Aaby,Peter Aaby,Marion Koopmans,Hendrik G. Stunnenberg,Reinout van Crevel,Mihai G. Netea,Mihai G. Netea +19 more
TL;DR: BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain, with a key role for IL-1β as a mediator of trained immunity responses.
Journal ArticleDOI
Macrophage Immunometabolism: Where Are We (Going)?
TL;DR: How the rapid growth of the immunometabolism field has improved the understanding of macrophage activation and at the same time has led to an increase in the appearance of contradictory observations is reviewed.
Journal ArticleDOI
α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming
Pu-Ste Liu,Haiping Wang,Xiaoyun Li,Tung Chao,Tony Teav,Stefan Christen,Stefan Christen,Giusy Di Conza,Wan-Chen Cheng,Chih Hung Chou,Magdalena Vavakova,Charlotte Muret,Koen Debackere,Koen Debackere,Massimiliano Mazzone,Massimiliano Mazzone,Hsien Da Huang,Sarah-Maria Fendt,Sarah-Maria Fendt,Julijana Ivanisevic,Ping-Chih Ho +20 more
TL;DR: New mechanistic regulations by which glutamine metabolism tailors the immune responses of macrophages through metabolic and epigenetic reprogramming are revealed.
Journal ArticleDOI
IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy.
TL;DR: This Review focuses on recent advances in the understanding of the transcriptional, chromatin-based and metabolic mechanisms that underlie IFNγ-mediated polarization of macrophages to an ‘M1-like’ state, which is characterized by increased pro-inflammatory activity and macrophage resistance to tolerogenic and anti-inflammatory factors.
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