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Willmann, K., & Moita, L. F. (2024). Physiologic disruption and metabolic reprogramming in infection and sepsis. Cell Metabolism, 36(5), 927–946. Added by: Dr. Enrique Feoli (03/09/2025, 02:13) Last edited by: Dr. Enrique Feoli (03/09/2025, 02:30) |
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| Resource type: Journal Article DOI: 10.1016/j.cmet.2024.02.013 ID no. (ISBN etc.): 1550-4131 BibTeX citation key: Willmann2024 View all bibliographic details  |
Categories: BioAcyl Corp Subcategories: Disease Tolerance Keywords: disease tolerance, immunometabolism, infection, Metabolic reprogramming, physiologic disruption, resistance, sepsis, surveillance immunity, therapy Creators: Moita, Willmann Collection: Cell Metabolism |
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| Abstract |
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Summary Effective responses against severe systemic infection require coordination between two complementary defense strategies that minimize the negative impact of infection on the host: resistance, aimed at pathogen elimination, and disease tolerance, which limits tissue damage and preserves organ function. Resistance and disease tolerance mostly rely on divergent metabolic programs that may not operate simultaneously in time and space. Due to evolutionary reasons, the host initially prioritizes the elimination of the pathogen, leading to dominant resistance mechanisms at the potential expense of disease tolerance, which can contribute to organ failure. Here, we summarize our current understanding of the role of physiological perturbations resulting from infection in immune response dynamics and the metabolic program requirements associated with resistance and disease tolerance mechanisms. We then discuss how insight into the interplay of these mechanisms could inform future research aimed at improving sepsis outcomes and the potential for therapeutic interventions.
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Key pathways of disease tolerance and resistance at the organismal, tissue, and cellular levels in sepsis Resistance mechanisms in immune cells activated in sepsis (neutrophils, macrophages, and T cells), and in endothelial cells rely on anabolic pathways (highlighted in orange) that enable biosynthesis and proliferation (including PPP activation) and consume energy rapidly made available by aerobic glycolysis (highlighted in orange). Inflammatory cytokines such as TNF, IL-1, and IL-6 promote metabolic rewiring, inhibiting OXPHOS and FAO. mTOR activation and AMPK suppression are hallmarks of this process, in addition to the activation of HIF1α and its targets (for example, PFK, LDH, and GLUT1). The mTORC1-HIF1α axis is also required for cytokine production and drives the upregulation of costimulatory molecules, while iNOS expression in response to HIF1α and inflammatory signals suppresses OXPHOS and FAO through ETC deactivation. Insulin resistance in the periphery, driven by feedback inhibition of insulin-PI3K-AKT mediated by mTORC1-HIF1α, leads to high glucose availability for resistance mechanisms. In disease tolerance mechanisms on the organismal, tissue, and cellular levels, catabolic processes are overrepresented and are colored in green.
On an organismal level, inflammatory mediators upregulated by infection activate the neuroendocrine HPA axis, which in turn regulates sickness behavior and metabolic adaptation through activating glucocorticoids, FGF21, and central catabolic circuits expressed in metabolically active tissue, including ATGL in the adipose tissue and PPARα and autophagy (through mTOR inhibition) in the liver. This FAO-promoting profile also includes the PPARα-dependent machinery for the import of fatty acids into mitochondria (CD36, CPT1, CPT2, and SLC25A20). This systemic profile resembling starvation response appears to be beneficial in sepsis, but part of sepsis pathophysiology constitutes a partial block of this response.
On the tissue level, specific disease tolerance mechanisms are predominant in each organ. In the lung, kidney, and liver, FAO-based mechanisms promote disease tolerance to sepsis, while the brain is protected by ketone bodies, and cardiac disease tolerance is supported by cardiac-resident macrophages and metabolites such as carnitine, low levels of lactose, and FGF21.
On the cellular level, disease tolerance can be mediated by homeostasis-promoting macrophages that rely on IL-10 and IL-4 signaling and their downstream targets such as the DDIT4 and PGC1β, which help to inhibit mTOR, promote OXPHOS, and induce mitophagy. α-Ketoglutarate from glutaminolysis can also promote FAO. Tissue repair is also regulated by iron excretion and retention and haem catabolism by macrophages. CypD is a checkpoint of T cell and NK cell metabolism and required for limiting tissue damage in response to influenza A virus.
TNF, tumor necrosis factor; AMPK, adenosine monophosphate-activated protein kinase; mTOR, mammalian target of rapamycin; HIF1α, hypoxia-inducible factor 1 alpha; PFK, phosphofructokinase; LDH, lactate dehydrogenase; GLUT1, glucose transporter 1; PPP, pentose phosphate pathway; FAO, fatty acid oxidation; ETC, electron transport chain, HMox1, heme oxygenase 1; iNOS, inducible nitric oxide synthase; HPA axis, hypothalamic-pituitary-adrenal axis; GC, glucocorticoid; FFA, free fatty acid; PM, plasma membrane; OMM, mitochondrial outer membrane; IMM, mitochondrial inner membrane; AKI, acute kidney injury; ROS, reactive oxygen species.
Added by: Dr. Enrique Feoli Last edited by: Dr. Enrique Feoli |