Sepsis Immunometabolism: From Defining Sepsis to Understanding How Energy Production Affects Immune Response

Abstract

Objectives: This review will examine current definitions and trends in sepsis management as well pathophysiologic mechanisms in animal and ex vivo studies that correlate decreased energy production with deranged inflammatory response during the septic process. Data Sources: The latest articles in the literature that focus on the role of immunometabolism and associated mechanisms in sepsis were selected. Study Selection: The most relevant, original articles were included in the review. Data Extraction: All pertinent data for sepsis definitions as well as changes in immunometabolic pathways during the septic process was reviewed and assessed for inclusion in this article. Data Synthesis: Sepsis is a major cause of multiple organ dysfunction. It is the principal cause of death resulting from infection and one of the most expensive conditions treated in the United States. Despite current efforts to accurately define sepsis, novel treatments and highly trained providers, mortality rates for sepsis remain high, prompting a need for further investigation of underlying immunometabolic mechanisms to identify potential treatment targets. The definition of sepsis has shifted and changed in the past few decades due to poorly defined criteria, as well as unclear guidelines for providers with regards to management of severe sepsis and septic shock. The early identification of patients with a systemic inflammatory response that will progress to septic shock is critical since recent traditional therapeutic approaches, such as early goal-directed therapy, IV immunoglobulin, and anti–tumor necrosis factor-α antibodies have failed. Conclusions: There are no effective anti-sepsis drug therapies due to complex inflammatory and metabolic interactions. Further studies regarding the interface between innate immunity and metabolism should be investigated to effectively address septic patient mortality rates.

The Effects of Biological Sex on Sepsis Treatments in Animal Models: A Systematic Review and a Narrative Elaboration on Sex- and Gender-Dependent Differences in Sepsis

“…Metabolic processes regulate the immune system during normal physiology, but these effects may be amplified during severely pathologic processes such as those which occur during sepsis. Failure to consider the role of metabolic dysfunction during sepsis may contribute to the lack of success in translational sepsis research ( 48 ). This section briefly discusses potential sex-dependent differences in the immune response and metabolic processes that may contribute to sex-dependent differences in sepsis.…”

“…Hyperinflammation observed in the acute phase of sepsis has been linked to metabolic changes such as energy deprivation, increased metabolic demand, and end-organ failure. The impairment of oxidative phosphorylation and the subsequent metabolic shift toward glycolysis are thought to be due to decreased expression of peroxisomal proliferator-activated receptor (PPAR)-γ (which mediates lipid and glucose metabolism) and impaired mitochondrial function (critical for oxidative phosphorylation and cell metabolism) ( 48 , 58 , 59 ). Interestingly, preclinical studies demonstrated that mitochondria in females have lower levels of oxidative stress (which was suppressed by ovariectomy) and higher levels of antioxidants and antioxidant enzymes ( 60 , 61 ).…”

Metabolic dysfunction and immunometabolism in COVID-19 pathophysiology and therapeutics

“…Immunometabolic pathways are modulated in part by the peroxisome proliferator-activated receptors (PPARs). These proteins are members of the nuclear receptor superfamily of transcriptional regulators and essential to glucose and lipid homeostasis [ 50 ]. PPARβ/δ and PPARγ play an important role in macrophage polarization [ 51 ].…”

“…In a mouse model, knockout of PPARγ increased IL-1β, IL-6, and TNF-α when exposed to lipopolysaccharide [ 52 ]. Unlike purely anti-inflammatory treatments, drugs targeting PPARs can have a dual effect on both immune and metabolic pathways [ 50 ]. Thiazolidinediones such as rosiglitazone and pioglitazone, both PPARγ agonists, improve cardiac function and overall mortality in animal models of sepsis and decrease the local inflammatory response by lowering IL-1β, TNF-α, and IL-6 levels [ 53 , 54 ].…”

Cellular and Exosomal Regulations of Sepsis-Induced Metabolic Alterations

“…Over the years several clinical trials of anti-inflammatory therapies such as the use of corticosteroids, activated protein C, tumor necrosis factor receptor Fc (TNFR-Fc) fusion protein, anti-tumor necrosis factor α (anti-TNF-α), thrombomodulin, and anti-interleukin1 receptor antagonist (IL-1ra) have failed to demonstrate the improvement of mortality [ 6 , 7 , 8 , 9 ]. With regards to immunomodulatory therapies to reverse immune paralysis, administration of IL-7 and inhibition of programmed cell death protein 1/programmed death ligand (PD-1/PD-L) interaction are promising investigational drugs, although their clinical effectiveness has yet to be shown [ 10 , 11 ]. On the other hand, granulocyte-macrophage colony-stimulating factor (GM-CSF) therapies have shown an effect to improve symptoms of adult patients with severe sepsis or cirrhosis by restoring innate immune responses [ 12 , 13 ] and pediatric patients with multiple organ dysfunction syndrome (MODS) by preventing nosocomial infection [ 14 ].…”