Nicotinamide pathways as the root cause of sepsis – an evolutionary perspective on macrophage energetic shifts

Suchard, Melinda; Savulescu, Dana

doi:10.1111/febs.15807

Cited by 13 publications

(7 citation statements)

References 112 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such sustained CD38 expression may be responsible for the depletion of cellular NAD + , leading to the exhaustion phenotype we observed in this current study. Indeed, we observed a drastic reduction of mitochondria respiration and elevated cellular ROS in monocytes with prolonged LPS challenges, another key feature of exhausted monocytes observed independently from septic models (40,41,59). Mitochondrial dysfunction has been directly associated with organ dysfunction in animal sepsis as well as septic patients (40).…”

Section: Discussionmentioning

confidence: 71%

Development of Exhausted Memory Monocytes and Underlying Mechanisms

Pradhan

Geng

et al. 2021

Front. Immunol.

View full text Add to dashboard Cite

Pathogenic inflammation and immuno-suppression are cardinal features of exhausted monocytes increasingly recognized in septic patients and murine models of sepsis. However, underlying mechanisms responsible for the generation of exhausted monocytes have not been addressed. In this report, we examined the generation of exhausted primary murine monocytes through prolonged and repetitive challenges with high dose bacterial endotoxin lipopolysaccharide (LPS). We demonstrated that repetitive LPS challenges skew monocytes into the classically exhausted Ly6Chi population, and deplete the homeostatic non-classical Ly6Clo population, reminiscent of monocyte exhaustion in septic patients. scRNAseq analyses confirmed the expansion of Ly6Chi monocyte cluster, with elevation of pathogenic inflammatory genes previously observed in human septic patients. Furthermore, we identified CD38 as an inflammatory mediator of exhausted monocytes, associated with a drastic depletion of cellular NAD+; elevation of ROS; and compromise of mitochondria respiration, representative of septic monocytes. Mechanistically, we revealed that STAT1 is robustly elevated and sustained in LPS-exhausted monocytes, dependent upon the TRAM adaptor of the TLR4 pathway. TRAM deficient monocytes are largely resistant to LPS-mediated exhaustion, and retain the non-classical homeostatic features. Together, our current study addresses an important yet less-examined area of monocyte exhaustion, by providing phenotypic and mechanistic insights regarding the generation of exhausted monocytes.

show abstract

Section: Discussionmentioning

confidence: 71%

Development of Exhausted Memory Monocytes and Underlying Mechanisms

Pradhan

Geng

et al. 2021

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…We also observed elevated tryptophan concentration in the 28dS group compared to the 28dD group; tryptophan protects the liver by reducing the pro-in ammatory cytokine levels [29]. The immunomodulatory enzyme, indoleamine 2,3-dioxygenase (IDO), controls tryptophan metabolism and correlates with hypotension in human septic shock [30,31]. The IDO-mediated tryptophan catabolism is associated with immune dysfunction and impaired microvascular reactivity in sepsis [32].…”

Section: Amino Acid Metabolismmentioning

confidence: 88%

Construction of the Metabolomics-Based Prognosis-Prediction Models for ICU Septic Patients

Ding

Tong²,

Song³

et al. 2022

SSRN Journal

View full text Add to dashboard Cite

Background: Global mortality related to sepsis remains unacceptably high in intensive care units (ICUs). Accurate prognostic evaluation of sepsis could effectively reduce the mortality of septic patients. Our goal is to present an effective and rapid method to assess the prognosis of sepsis.Methods: We included 96 septic patients according to the sepsis 3.0 in ICU, who were grouped into survival and death groups according to 28-day, hospital, and 90-day prognosis. Liquid chromatography/mass spectrometry was performed to detect the metabolite changes in plasma. Multivariate logistic regression models, using differential metabolites and clinical indicators within 24 h after diagnosis of sepsis, were used to construct the prediction models for 28-day, hospital, and 90-day prognosis in sepsis.Results: Metabolic pro les related to 28-day, hospital, and 90-day prognosis were signi cantly different between the survival and the death group. Speci cally, 13, 4, and 29 primary differential metabolites related to amino acid metabolism and fatty acid metabolism were identi ed between the survival and death group at 28-day, hospital, and 90-day prognosis, respectively. Further, we found that model 1 including indoleacetic acid, 3-methylene-indolenine, heart rate, respiratory support, and application of pressure drugs; model 2 including lymphocyte count, alkaline phosphatase, SOFA, and L-alpha-amino-1H-pyrrole-1-hexanoic acid; model 3 including pyrrolidine, dopamine, heart rate, respiratory support, and application of pressure drugs, could predict 28-day, hospital, and 90-day prognosis of sepsis with a sensitivity of 75.51%, 73.58%, and 83.33%, speci city of 78.72%, 72.09%, and 76.19%, the area under the receiver operating characteristics curve of 0.881, 0.830, 0.892, respectively.Conclusions: This research could be used to predict the 28-day, hospital, and 90-day prognosis of septic patients based on differential metabolites and clinical parameters, and could also be used to develop novel sepsis-treatment methods.

show abstract

“…Nicotinamide is a small molecule that amplifies the antimicrobial potency of AMPs; for example, nicotinamide cooperatively augments the human LL37 antimicrobial peptide against S. aureus. [71] Nicotinamide is also immunomodulatory by inhibiting T-Cell exhaustion and increasing differentiation of CD8 effector T-Cells, thereby reducing pro-inflammatory cytokine production and inflammatory responses in multiple cell types and tissues. [72] 4-Hydroxybutyrate (4-HB): 4-HB is a short chain fatty acid endogenously biosynthesized during lipid metabolism by reduction of succinic semialdehyde via succinic semialdehyde reductase.…”

Section: Metalsmentioning

confidence: 99%

Endogenous Antimicrobial‐Immunomodulatory Molecules: Networking Biomolecules of Innate Immunity

Weaver

2024

ChemBioChem

View full text Add to dashboard Cite

Endogenous antimicrobial‐immunomodulatory molecules (EAIMs) are essential to immune‐mediated human health and evolution. Conventionally, antimicrobial peptides (AMPs) have been regarded as the dominant endogenous antimicrobial molecule; however, AMPs are not sufficient to account for the full spectrum of antimicrobial‐immunomodulatory duality occurring within the human body. The threat posed by pathogenic microbes is pervasive with the capacity for widespread impact across many organ systems and multiple biochemical pathways; accordingly, the host needs the capacity to react with an equally diverse response. This can be attained by having EAIMs that traverse the full range of molecular size (small to large molecules) and structural diversity (including molecules other than peptides). This review identifies multiple molecules (peptide/protein, lipid, carbohydrate, nucleic acid, small organic molecule, and metallic cation) as EAIMs and discusses the possibility of cooperative, additive effects amongst the various EAIM classes during the host response to a microbial assault. This comprehensive consideration of the full molecular diversity of EAIMs enables the conclusion that EAIMs constitute a previously uncatalogued structurally diverse and collectively underappreciated immuno‐active group of integrated molecular responders within the innate immune system’s first line of defence.

show abstract

Nicotinamide pathways as the root cause of sepsis – an evolutionary perspective on macrophage energetic shifts

Cited by 13 publications

References 112 publications

Development of Exhausted Memory Monocytes and Underlying Mechanisms

Development of Exhausted Memory Monocytes and Underlying Mechanisms

Construction of the Metabolomics-Based Prognosis-Prediction Models for ICU Septic Patients

Endogenous Antimicrobial‐Immunomodulatory Molecules: Networking Biomolecules of Innate Immunity

Contact Info

Product

Resources

About