Metabolic adaptation establishes disease tolerance to sepsis
Open accessAbstract
Sepsis is an often lethal syndrome resulting from maladaptive immune and metabolic responses to infection, compromising host homeostasis. Disease tolerance is a defense strategy against infection that preserves host homeostasis without exerting a direct negative impact on pathogens. Here, we demonstrate that induction of the iron-sequestering ferritin H chain (FTH) in response to polymicrobial infections is critical to establish disease tolerance to sepsis. The protective effect of FTH is exerted via a mechanism that counters iron-driven oxidative inhibition of the liver glucose-6-phosphatase (G6Pase), and in doing so, sustains endogenous glucose production via liver gluconeogenesis. This is required to prevent the development of hypoglycemia that otherwise compromises disease tolerance to sepsis. FTH overexpression or ferritin administration establish disease tolerance therapeutically. In conclusion, disease tolerance to sepsis relies on a crosstalk between adaptive responses controlling iron and glucose metabolism, required to maintain blood glucose within a physiologic range compatible with host survival.
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HO-1 exerts cytoprotective effects by reducing the pro-oxidative activity of heme and by re-programming metabolic traits, thereby limiting tissue damage in inflammatory processes, including sepsis.
“Thus, HO-1 exerts cytoprotective effects by reducing the pro-oxidative activity of heme and by re-programming metabolic traits, thereby limiting tissue damage in the course of inflammatory processes, including sepsis (Gozzelino et al., 2010; Weis et al., 2017).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Weis et al., 2017
Heme oxygenase-1 induces a stage of tolerance to severe infection by avoiding tissue damage and securing nutritional delivery for affected cells.
“It has also be demonstrated that iron handling enzymes, such as heme oxygenase-1, which degrades free heme and reduces intravascular radical formation, induce a stage of tolerance to severe infection by avoiding tissues damage and by securing nutritional delivery for affected cells [188].”
From Iron in immune cell function and host defense (2021) · cites this paper as [188]
Heme oxygenase-1 degrades free heme and reduces intravascular radical formation.
“It has also be demonstrated that iron handling enzymes, such as heme oxygenase-1, which degrades free heme and reduces intravascular radical formation, induce a stage of tolerance to severe infection by avoiding tissues damage and by securing nutritional delivery for affected cells [188].”
From Iron in immune cell function and host defense (2021) · cites this paper as [188]
Ferritin induction is essential for host survival of extracellular bacterial infections and Plasmodium infection.
“Induction of ferritin expression is essential to sustain host survival of extracellular bacterial infections (52) as well as Plasmodium infection (53).”
From Innate Nutritional Immunity (2018) · cites this paper as [52]
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A STUDY OF IRON-INDUCED LIVER DAMAGE
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“…oxidative modifications in G6PC1 and G6PT1 thiol (SH) groups (Clottes and Burchell, 1998), which represses G6Pase expression and/or activity (Witzleben and Chaffey, 1962), this does not appear to be involved in the mechanism in which heme and TNF repress G6Pase and/or the mechanism in which…”
Metabolic adaptation to tissue iron overload confers tolerance to malaria
Gozzelino, R., Andrade, B. B., Larsen, R., Luz, N. F., Vanoaica, L., Seixas, E., Coutinho, A., Cardoso, S., Rebelo, S., Poli, M., et al. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.10.011 · Cited by 3 · cited 11× · see citing works
“CMV-pLpASR+ßGal (LacZ) Berberat et al., 2003; Gozzelino et al., 2012 Kind gift from Paolo Arosio, University of Brescia, Italy pAC.”
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Mechanisms controlling cellular and systemic iron homeostasis
Galy, B., Conrad, M., & Muckenthaler, M. U. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00648-1 · Cited by 806 · see citing works
GDF15 Is an Inflammation-Induced Central Mediator of Tissue Tolerance
Luan, H. H., Wang, A., Hilliard, B. K., Carvalho, F., Rosen, C. E., Ahasic, A. M., Herzog, E. L., Kang, I., Pisani, M. A., Yu, S., et al. (2019) · Cell · doi:10.1016/j.cell.2019.07.033 · Cited by 527 · see citing works
“, 2016) and very low levels due to lack of gluconeogenesis (Weis et al., 2017) resulted in mortality, triglyceride levelsmust bemaintained in the right range to have a protective effect.”
SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression
Cecchini, R., & Cecchini, A. L. (2020) · Medical Hypotheses · doi:10.1016/j.mehy.2020.110102 · Cited by 402 · see citing works
“In addition, administration of apoferritin (ferritin that is not combined with iron) and the induction of the expression of ferritin heavy chain, decreases CLP mice mortality [32].”
BackgroundThe role of NCOA4-mediated ferritinophagy in health and disease
Santana-Codina, N., & Mancias, J. D. (2018) · Pharmaceuticals · doi:10.3390/ph11040114 · Cited by 410 · see citing works
“Iron is required in multiple biological processes [1] including oxygen binding and transport [2], ATP production (as a cofactor in the citric acid cycle and electron transport) [3], and DNA biosynthesis and repair [4,5].”
BackgroundSepsis therapies: learning from 30 years of failure of translational research to propose new leads
Cavaillon, J., Singer, M., & Skirecki, T. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.201810128 · Cited by 318 · see citing works
“Notably, sepsis non-survivors are characterized by subnormal levels of muscle ATP (Brealey et al, 2002), while maintenance of hepatic gluconeogenesis was shown to be crucial in establishing disease tolerance (Weis et al, 2017).”
BackgroundThe Role of Iron Regulation in Immunometabolism and Immune-Related Disease
Cronin, S. J. F., Woolf, C. J., Weiss, G., & Penninger, J. M. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00116 · Cited by 299 · see citing works
Origin and function of stress-induced IL-6 in murine models
Qing, H., Desrouleaux, R., Israni-Winger, K., Mineur, Y. S., Fogelman, N., Zhang, C., Rashed, S., Palm, N. W., Sinha, R., Picciotto, M. R., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.054 · Cited by 303 · see citing works
“The mechanism underlying this phenomenon is unclear, but likely is a result of stressinduced IL6-dependent metabolic re-programming similar to that which has been previously published by our group and others (Ganeshan et al., 2019; Luan et al., 2019; Wang et al., 2016; Wang A, 2019; Weis et al., 2017).”
The Role of NCOA4-Mediated Ferritinophagy in Ferroptosis
Santana-Codina, N., Gikandi, A., & Mancias, J. D. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-62026-4_4 · Cited by 315 · see citing works
Energetic Trade-Offs and Hypometabolic States Promote Disease Tolerance
Ganeshan, K., Nikkanen, J., Man, K., Leong, Y. A., Sogawa, Y., Maschek, J. A., Van Ry, T., Chagwedera, D. N., Cox, J. E., & Chawla, A. (2019) · Cell · doi:10.1016/j.cell.2019.01.050 · Cited by 286 · see citing works
Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last?
Wyngene, L. V., Vandewalle, J., & Libert, C. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201708712 · Cited by 264 · see citing works
“According to this study, gluconeogenesis in the liver is hampered during sepsis due to iron-driven oxidative inhibition of glucose-6-phosphatase (Weis et al, 2017).”
BackgroundDouble-edge sword roles of iron in driving energy production versus instigating ferroptosis
Zhang, S., Xin, W., Anderson, G. J., Li, R., Gao, L., Chen, S., Zhao, J., & Liu, S. (2022) · Cell Death and Disease · doi:10.1038/s41419-021-04490-1 · Cited by 243 · see citing works
“Furthermore, the transcription of gluconeogenic genes, including G6Pase, can be downregulated by heme or heme-derived iron [18].”
BackgroundTucey, T. M., Verma, J., Harrison, P. F., Snelgrove, S. L., Lo, T. L., Scherer, A. K., Barugahare, A. A., Powell, D., Wheeler, R. T., Hickey, M. J., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.03.019 · Cited by 228 · see citing works
“…supplementation predominantly maintains macrophage function and ensures tissue homeostasis during C. albicans infection, similarly to the effects of glucose on tissue and organismal homeostasis that have been shown recently for bacterial and viral infection (Wang et al., 2016; Weis et al., 2017).”
BackgroundThe role of macrophages polarization in sepsis-induced acute lung injury
Wang, Z., & Wang, Z. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1209438 · Cited by 219 · see citing works
“GADD34/IKKb LPS intraperitoneally 16h inhibit M1-like phenotype (5)”
BackgroundThe mechanism of ferroptosis and its related diseases
Feng, S., Tang, D., Wang, Y., Li, X., Bao, H., Tang, C., Dong, X., Li, X., Yang, Q., Yan, Y., et al. (2023) · Molecular Biomedicine · doi:10.1186/s43556-023-00142-2 · Cited by 224 · see citing works
Sanchez, K. K., Chen, G. Y., Schieber, A. M. P., Redford, S. E., Shokhirev, M. N., Leblanc, M., Lee, Y. M., & Ayres, J. S. (2018) · Cell · doi:10.1016/j.cell.2018.07.016 · Cited by 175 · see citing works
“A recent study has suggested that liver iron sequestration regulates blood glucose levels by inducing ferritin to maintain liver gluconeogenesis during sepsis (Weis et al., 2017).”
Pro-inflammatory Actions of Heme and Other Hemoglobin-Derived DAMPs
Bozza, M. T., & Jeney, V. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01323 · Cited by 205 · see citing works
“Heme reduces blood glucose levels dependently of TLR4, contributing to the severity of sepsis, while FTH reverts this effect contributing to glucose and tissue homeostasis (25).”
BackgroundMetabolic Alterations in Sepsis
Wasyluk, W., & Zwolak, A. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10112412 · Cited by 202 · see citing works
“However, hepatic gluconeogenesis has been shown to be a necessary pathway to avoid fatal hypoglycemia in response to acute bacterial infection [102].”
BackgroundMiao, R., Fang, X., Zhang, Y., Wei, J., Zhang, Y., & Tian, J. (2023) · Cell Death & Disease · doi:10.1038/s41419-023-05708-0 · Cited by 192 · see citing works
“FTH maintains endogenous glucose production, through hepatic gluconeogenesis, which is necessary for hypoglycemic prevention [58].”
BackgroundIron in immune cell function and host defense
Haschka, D., Hoffmann, A., & Weiss, G. (2021) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2020.12.005 · Cited by 188 · see citing works
Neutrophil extracellular traps drive inflammatory pathogenesis in malaria
Knackstedt, S. L., Georgiadou, A., Apel, F., Abed, U. A., Moxon, C. A., Cunnington, A. J., Raupach, B., Cunningham, D., Langhorne, J., Krüger, R., et al. (2019) · Science Immunology · doi:10.1126/sciimmunol.aaw0336 · Cited by 171 · see citing works
“Quantification of plasma heme Heme was quantified using the formic acid assay (92).”
MethodLong-term reprogramming of the innate immune system
Domínguez‐Andrés, J., & Netea, M. G. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.mr0318-104r · Cited by 176 · see citing works
Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR
Mogilenko, D. A., Haas, J. T., L’homme, L., Fleury, S., Quemener, S., Levavasseur, M., Becquart, C., Wartelle, J., Bogomolova, A., Pineau, L., et al. (2019) · Cell · doi:10.1016/j.cell.2019.03.018 · Cited by 171 · see citing works
Ferritin: An Inflammatory Player Keeping Iron at the Core of Pathogen-Host Interactions
Moreira, A. C., Mesquita, G., & Gomes, M. S. (2020) · Microorganisms · doi:10.3390/microorganisms8040589 · Cited by 166 · see citing works
Disease Tolerance as an Inherent Component of Immunity
Martins, R., Carlos, A. R., Braza, F., Thompson, J. A., Bastos-Amador, P., Ramos, S., & Soares, M. P. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041739 · Cited by 149 · see citing works
“This is avoided in part by a host metabolic responsewhere iron neutralization by ferritin promotes hepatic glucose production via a mechanism that induces the transcription of the glucose-6-phosphatase (G6PC1) gene, promoting glycogenolysis and gluconeogenesis and establishing disease tolerance to bacterial infections…”
BackgroundInfluentialThe role of iron in host–microbiota crosstalk and its effects on systemic glucose metabolism
Mayneris‐Perxachs, J., Moreno‐Navarrete, J. M., & Fernández‐Real, J. M. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-022-00721-3 · Cited by 158 · see citing works
Shankar‐Hari, M., Calandra, T., Soares, M. P., Bauer, M. W., Wiersinga, W. J., Prescott, H. C., Knight, J. C., Baillie, J. K., Bos, L. D. J., Derde, L. P. G., et al. (2024) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(23)00468-x · Cited by 142 · see citing works
Trained innate immunity, long-lasting epigenetic modulation, and skewed myelopoiesis by heme
Jentho, E., Ruiz-Moreno, C., Novakovic, B., Kourtzelis, I., Megchelenbrink, W., Martins, R., Chavakis, T., Soares, M. P., Kalafati, L., Guerra, J., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2102698118 · Cited by 133 · see citing works
“Polymicrobial sepsis was induced using a well-characterized, standardized human stool suspension (peritoneal contamination and infection) (7).”
MethodMechanisms of Hemolysis During Sepsis
Effenberger‐Neidnicht, K., & Hartmann, M. (2018) · Inflammation · doi:10.1007/s10753-018-0810-y · Cited by 122 · see citing works
Glucocorticoids in Sepsis: To Be or Not to Be
Vandewalle, J., & Libert, C. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01318 · Cited by 123 · see citing works
Núñez, G., Sakamoto, K., & Soares, M. P. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1800325 · Cited by 115 · see citing works
“Induction of ferritin expression is essential to sustain host survival of extracellular bacterial infections (52) as well as Plasmodium infection (53).”
BackgroundSelf-citationEmerging and Dynamic Biomedical Uses of Ferritin
Chiou, B., & Connor, J. R. (2018) · Pharmaceuticals · doi:10.3390/ph11040124 · Cited by 119 · see citing works
“also looked at this metabolic adaptation in sepsis, a devastating syndrome resulting from a maladaptive host response to infection [108].”
BackgroundBeyer, D., Hoff, J., Sommerfeld, O., Zipprich, A., Gaßler, N., & Press, A. T. (2022) · Molecular Medicine · doi:10.1186/s10020-022-00510-8 · Cited by 122 · see citing works
“Glucose deregulation seems to be a key feature in metabolic failure (Weis et al. 2017).”
BackgroundPathophysiological role of respiratory dysbiosis in hospital-acquired pneumonia
Roquilly, A., Torres, A., Villadangos, J. A., Netea, M. G., Dickson, R. P., Becher, B., & Asehnoune, K. (2019) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(19)30140-7 · Cited by 107 · see citing works
Iron homeostasis and disorders revisited in the sepsis
Liu, Q., Wu, J., Zhang, X., Wu, X., Zhao, Y., & Ren, J. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.01.025 · Cited by 112 · see citing works
Ferritin Light Chain Confers Protection Against Sepsis-Induced Inflammation and Organ Injury
Zarjou, A., Black, L. M., McCullough, K., Hull, T. D., Esman, S. K., Boddu, R., Varambally, S., Chandrashekar, D. S., Feng, W., Arosio, P., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00131 · Cited by 106 · see citing works
“recently described how FtH mediated metabolic adaptation markedly improves disease tolerance to sepsis (58).”
BackgroundFerritin self-assembly, structure, function, and biotechnological applications
Sudarev, V. V., Dolotova, S. M., Bukhalovich, S. M., Bazhenov, S. V., Ryzhykau, Y. L., Uversky, V. N., Bondarev, N. A., Osipov, S. D., Mikhailov, A. E., Kuklina, D. D., et al. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.10.126 · Cited by 106 · see citing works
Methods for the study of innate immunity in Drosophila melanogaster
Troha, K., & Buchon, N. (2019) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.344 · Cited by 102 · see citing works
“Disease tolerance mechanisms involve many different biological processes, from metabolic adaptation and stress responses to tissue repair (Soares, Gozzelino, & Weis, 2014; Troha et al., 2018; Weis et al., 2017).”
BackgroundThe gut microbiome alters immunophenotype and survival from sepsis
Fay, K. T., Klingensmith, N., Chen, C.-W., Zhang, W., Sun, Y.-N., Morrow, K. N., Liang, Z., Burd, E. M., Ford, M. L., & Coopersmith, C. M. (2019) · The FASEB Journal · doi:10.1096/fj.201802188r · Cited by 88 · see citing works
“The mechanisms underlying disease tolerance are complex, but damage control allows for the preservation of functional output of parenchymal tissue, thereby maintaining homeostatic parameters within an acceptable range (43).”
BackgroundTGF-β uncouples glycolysis and inflammation in macrophages and controls survival during sepsis
Gauthier, T., Yao, C., Dowdy, T., Jin, W., Lim, Y.-J., Patiño, L. C., Liu, N., Ohlemacher, S. I., Bynum, A., Kazmi, R., et al. (2023) · Science Signaling · doi:10.1126/scisignal.ade0385 · Cited by 109 · see citing works
“A concept termed tissue tolerance has emerged that describes the idea that the ability of a tissue to remain tolerant to infection, rather than clearing the pathogen and mounting an inflammatory response, is crucial for the survival of the host (74, 75).”
BackgroundMemory-Like Inflammatory Responses of Microglia to Rising Doses of LPS: Key Role of PI3Kγ
Lajqi, T., Lang, G.-P., Haas, F., Williams, D. L., Hudalla, H., Bauer, M. W., Groth, M., Wetzker, R., & Bauer, R. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02492 · Cited by 98 · see citing works
Sepsis: a failing starvation response
Vandewalle, J., & Libert, C. (2022) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2022.01.006 · Cited by 101 · see citing works
“33 Weis, S. et al. (2017) Metabolic Adaptation Establishes Disease Tolerance to Sepsis.”
BackgroundLi, J., Feng, Y., Li, Y., He, P., Zhou, Q.-Y., Tian, Y., Yao, R.-Q., & Yao, Y.-M. (2024) · Cell Proliferation · doi:10.1111/cpr.13621 · Cited by 102 · see citing works
“5 By contrast, iron overload is inclined to jeop-ardise organelle and even tissues owing to the production of reactive oxygen species (ROS) generated via the Fenton reaction of the Haber – Weiss cycle, a process newly defined as ferroptosis.”
BackgroundMetabolic Adaptations to Infections at the Organismal Level
Troha, K., & Ayres, J. S. (2020) · Trends in Immunology · doi:10.1016/j.it.2019.12.001 · Cited by 97 · see citing works
“For example, regulation of host iron metabolism was found to be crucial to confer disease tolerance in murine models of malaria and polymicrobial sepsis (76, 77).”
BackgroundChen, X., Sunkel, B. D., Wang, M., Kang, S., Wang, T., Gnanaprakasam, J. R., Liu, L., Cassel, T., Scott, D. A., Muñoz-Cabello, A. M., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abm8161 · Cited by 93 · see citing works
“…pressures on host immune cells’ metabolic fitness and metabolic plasticity, allowing immune cells to maintain homeostasis while remaining ready to mount rapid responses under diverse metabolic and immune conditions (Slack et al., 2015; Troha and Ayres, 2020; Weinberg, 1975; Weis et al., 2017).”
BackgroundWu, R., Chen, X., Kang, S., Wang, T., Gnanaprakasam, J. R., Yao, Y., Liu, L., Zheng, S. G., Fan, G., Burns, M. R., et al. (2020) · Science Advances · doi:10.1126/sciadv.abc4275 · Cited by 87 · see citing works
Immunometabolism and Sepsis: A Role for HIF?
Fitzpatrick, S. F. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00085 · Cited by 84 · see citing works
“Recent research has shown that metabolic deregulation also plays a vital role in sepsis progression (Weis et al., 2017).”
BackgroundRemembering Pathogen Dose: Long-Term Adaptation in Innate Immunity
Bauer, M. W., Weis, S., Netea, M. G., & Wetzker, R. (2018) · Trends in Immunology · doi:10.1016/j.it.2018.04.001 · Cited by 83 · see citing works
Renal control of disease tolerance to malaria
Ramos, S., Carlos, A. R., Sundaram, B., Jeney, V., Ribeiro, A. C., Gozzelino, R., Bank, C., Gjini, E., Braza, F., Martins, R., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1822024116 · Cited by 77 · see citing works
“5 A and B) (9, 25), suggesting that the ferroxidase activity of FTH is required to counter the cytotoxic effects of labile heme and H2O2 in human RPTEC.”
MethodHemolysis transforms liver macrophages into antiinflammatory erythrophagocytes
Pfefferlé, M., Ingoglia, G., Schaer, C. A., Yalamanoglu, A., Buzzi, R. M., Dubach, I. L., Tan, G., López-Cano, E. Y., Schulthess-Lutz, N., Hansen, K., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci137282 · Cited by 75 · see citing works
“NRF2 can suppress inflammation by at least four mutually interacting mechanisms including modulation of reactive oxygen species-dependent signaling (37, 41), transcriptional repression (42) , interference with NF-κB (43) , post-transcriptional modulation of inflammatory signaling genes (44, 45), or via enhance…”
BackgroundInfluentialTetracycline Antibiotics Induce Host-Dependent Disease Tolerance to Infection
Colaço, H. G., Barros, A., Neves‐Costa, A., Seixas, E., Pedroso, D. C. S., Velho, T. R., Willmann, K. L., Faísca, P., Grabmann, G., Yi, H., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.09.011 · Cited by 80 · see citing works
A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis
Loft, A., Schmidt, S. F., Caratti, G., Stifel, U., Havelund, J., Sekar, R., Kwon, Y., Sulaj, A., Chow, K. K., Alfaro, A. J., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.01.004 · Cited by 76 · see citing works
Characterization of plasma labile heme in hemolytic conditions
Gouveia, Z., Carlos, A. R., Yuan, X., Aires‐da‐Silva, F., Stocker, R., Maghzal, G. J., Leal, S. S., Gomes, C. M., Todorovic, S., Iranzo, O., et al. (2017) · The FEBS Journal · doi:10.1111/febs.14192 · Cited by 70 · see citing works
“This endows labile heme with pro-inflammatory [16–20], vasoactive [21], and cytotoxic [10,22–25] effects, while also regulating metabolism [26] and interfering with Gouveia et al.”
BackgroundCombined glucocorticoid resistance and hyperlactatemia contributes to lethal shock in sepsis
Vandewalle, J., Timmermans, S., Paakinaho, V., Vancraeynest, L., Dewyse, L., Vanderhaeghen, T., Wallaeys, C., Wyngene, L. V., Looveren, K. V., Nuyttens, L., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.07.002 · Cited by 78 · see citing works
Recent advances in understanding and managing sepsis
Berg, D., & Gerlach, H. (2018) · F1000Research · doi:10.12688/f1000research.15758.1 · Cited by 74 · see citing works
Zhang, J., Chen, X., Hong, J., Tang, A., Liu, Y., Xie, N., Nie, G., Yan, X., & Liang, M. (2020) · Science China Life Sciences · doi:10.1007/s11427-020-1795-4 · Cited by 76 · see citing works
Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction
Mainali, R., Zabalawi, M., Long, D. L., Buechler, N. L., Quillen, E. E., Key, C.-C., Zhu, X., Parks, J. S., Furdui, C. M., Stacpoole, P. W., et al. (2021) · eLife · doi:10.7554/elife.64611 · Cited by 76 · see citing works
“The results of this study fill a gap in understanding how sepsis at the molecular level alters liver metabolism and expand the current concepts on physiology and pathophysiology of resistance and tolerance of hepatocyte during sepsis (Weis et al., 2017; Soares et al., 2017).”
BackgroundDAMPs and Innate Immune Training
Jentho, E., & Weis, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.699563 · Cited by 72 · see citing works
Glucose metabolism mediates disease tolerance in cerebral malaria
Wang, A., Huen, S. C., Luan, H. H., Baker, K., Rinder, H. M., Booth, C. J., & Medzhitov, R. M. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1806376115 · Cited by 72 · see citing works
“There are now a couple of examples where disease tolerance is mechanistically linked to metabolism (9, 10).”
BackgroundFerritin regulates organismal energy balance and thermogenesis
Blankenhaus, B., Braza, F., Martins, R., Bastos-Amador, P., González‐García, I., Carlos, A. R., Mahú, I., Faísca, P., Nunes, J. M., Ventura, P., et al. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.03.008 · Cited by 64 · see citing works
Modulation of iron homeostasis with hepcidin ameliorates spontaneous murine lupus nephritis
Scindia, Y. M., Wlazlo, E., Ghias, E., Cechova, S., Loi, V., Leeds, J. T., Ledesma, J., Helen, C., & Swaminathan, S. (2020) · Kidney International · doi:10.1016/j.kint.2020.01.025 · Cited by 61 · see citing works
Apoptotic cell therapy for cytokine storm associated with acute severe sepsis
Karbian, N., Abutbul, A., el-Amore, R., Eliaz, R., Beeri, R., Reicher, B., & Mevorach, D. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-02748-8 · Cited by 63 · see citing works
Cold exposure protects from neuroinflammation through immunologic reprogramming
Spiljar, M., Steinbach, K., Rigo, D., Suárez-Zamorano, N., Wagner, I., Hadadi, N., Vincenti, I., Pagé, N., Klimek, B., Rochat, M.-A., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.10.002 · Cited by 64 · see citing works
Nahrendorf, W., Ivens, A. C., & Spence, P. J. (2021) · eLife · doi:10.7554/elife.63838 · Cited by 62 · see citing works
“There is a growing body of evidence that shows mechanisms of disease tolerance are required to survive a first malaria episode: for example, acute infection causes hypoglycaemia and so the ability to maintain blood glucose levels within dynamic range – in crosstalk with iron metabolism (Weis et al., 2017) – can determ…”
BackgroundNCOA4 maintains murine erythropoiesis via cell autonomous and non-autonomous mechanisms
Santana-Codina, N., Gableske, S., del Rey, M. Q., Małachowska, B., Jedrychowski, M. P., Biancur, D. E., Schmidt, P. J., Fleming, M. D., Fendler, W. M., Harper, J. W., et al. (2019) · Haematologica · doi:10.3324/haematol.2018.204123 · Cited by 61 · see citing works
“Iron is an essential element for life, required in a diverse set of processes including oxygen binding and transport,(1) electron transport,(2) and DNA synthesis and repair.(3,4)”
BackgroundCentral metabolic interactions of immune cells and microbes: prospects for defeating infections
Traven, A., & Naderer, T. (2019) · EMBO Reports · doi:10.15252/embr.201947995 · Cited by 59 · see citing works
“Glucose supplementation rescued mice that failed to maintain blood glucose levels after polymicrobial infection [115].”
InfluentialTreatment Advances in Sepsis and Septic Shock: Modulating Pro- and Anti-Inflammatory Mechanisms
Marques, A. M., Torre, C., Pinto, R. M. A., Sepodes, B. M. N., & Rocha, J. P. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12082892 · Cited by 65 · see citing works
“No sepsis-specific therapies exist, and new approaches are urgently needed [16,17].”
BackgroundPersistent Toll-like receptor 7 stimulation induces behavioral and molecular innate immune tolerance
Michaelis, K. A., Norgard, M. A., Levasseur, P. R., Olson, B. G., Burfeind, K. G., Buenafe, A. C., Zhu, X., Jeng, S., McWeeney, S. K., & Marks, D. L. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.09.004 · Cited by 58 · see citing works
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The immunology of sepsis: translating new insights into clinical practice
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“Aerobic glycolysis rapidly generates biosynthetic precursor molecules, can function under otherwise adverse hypoxic or acidic microenvironments, entraps T cells at inflammatory sites and may provide systemic control via blood glucose levels (22, 26).”
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“A recent study demonstrated that ferritin was also essential to establish a host defense against pathogens, and the ferritin performed a function via preventing glucose consumption in liver [8].”
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BackgroundHepatic FGF21 preserves thermoregulation and cardiovascular function during bacterial inflammation
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“The underlying mechanisms might be amenable to therapy (1, 6, 7).”
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“6,7 Lipid droplet (LD) accumulation and oxidative stress are recurrent consequences of sepsis-induced metabolic reprogramming.”
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Labile heme impairs hepatic microcirculation and promotes hepatic injury
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- Authors
- Weis, S., Carlos, A. R., Moita, M. R., Singh, S., Blankenhaus, B., Cardoso, S., Larsen, R., Rebelo, S., Schäuble, S., Del Barrio, L., Mithieux, G., Rajas, F., Lindig, S., Bauer, M., & Soares, M. P.
- Affiliations
- Jena University Hospital (DE)
- Instituto Gulbenkian de Ciência (PT)
- Friedrich Schiller University Jena (DE)
- Lyon 1 Université (FR)
- Corresponding author
- Soares, Miguel P.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 169
- Issue
- 7
- Pages
- 1263-1275.e14
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5480394
- OpenAlex
- W2626179297
- Semantic Scholar
- 42077ae8d50b6b90713506e72f054f67dc033673
- Cited by
- 284
- References
- 57
- Citations by year
- 2026: 28 · 2025: 34 · 2024: 33 · 2023: 27 · 2022: 25 · 2021: 30 · 2020: 33 · 2019: 37 · 2018: 29 · 2017: 8
- FWCI
- 22.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Fundação para a Ciência e Tecnologia (PTDC/SAU-TOX/116627/2010, HMSP-ICT/0018/2011, SFRH/BPD/101608/2014)
- European Community 7th Framework (ERC-2011-AdG 294709-DAMAGECONTROL)
- Deutsche Forschungsgemeinschaft (DFG (WE 4971/3)
- German Federal Ministry of Education and Research (01EO1002)
- Meta-ZIK (03Z2J52)
- German Ministry for Research and Education e:Med initiative GlioPATH (FKZ 01ZX1402C)
- French National Research Agency (ANR-11-BSV1-009, ANR-15-CE14-0026-03)
- Medical Research Foundation (DRM20101220448)
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- sepsis, disease tolerance, iron sequestration, glucose-6-phosphatase, gluconeogenesis, hepatic glucose production, hypoglycemia, co-infection, iron metabolism, glucose metabolism, host homeostasis
- MeSH terms
- Animals, Apoferritins, Ceruloplasmin, Gluconeogenesis, Glucose, Glucose-6-Phosphatase, Iron, Mice, Inbred C57BL, Sepsis, Mice
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