The Immunological Landscape of Sepsis: From Cytokine Storm to Immune Paralysis
Abstract
Sepsis is a dynamic and heterogeneous syndrome characterized by a dysregulated host response to infection, leading to concurrent hyperinflammation and profound immunosuppression. Early recognition of pathogen- and damage-associated molecular patterns triggers extensive activation of NF-κB, JAK/STAT, and MAPK pathways, resulting in a cytokine storm, metabolic reprogramming, and endothelial dysfunction. Mitochondrial impairment, glycocalyx degradation, and excessive neutrophil activity further propagate organ injury and microcirculatory collapse. Simultaneously, widespread apoptosis and exhaustion of lymphocytes culminate in immune paralysis and increased susceptibility to secondary infections. Advances in transcriptomics, proteomics, metabolomics, and machine-learning–based classification have uncovered distinct immune endotypes of sepsis, providing the foundation for precision medicine. Emerging immunomodulatory therapies—including IL-7, GM-CSF, and immune checkpoint inhibitors—aim to restore immune function in selected subgroups. Ultimately, sepsis must be viewed as a multifaceted immunometabolic disorder requiring individualized diagnosis, monitoring, and treatment approaches.
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[14] Fang J, Ding H, Huang J, Liu W, Hong T, Yang J, et al. Mac-1 blockade impedes adhesion-dependent neutrophil extracellular trap formation and ameliorates lung injury in LPS-induced sepsis. Front Immunol. 2025; 16:1548913.
[15] Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol. 2007; 5(8):577-82.
[16] van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. 2017; 17(7):407-20.
[17] Hotchkiss RS, Colston E, Yende S, Crouser ED, Martin GS, Albertson T, et al. Immune checkpoint inhibition in sepsis: a Phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab. Intensive Care Med. 2019;45(10):1360-1371.
[18] Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011; 306(23):2594-605.
[19] Davenport EE, Burnham KL, Radhakrishnan J, Humburg P, Hutton P, Mills TC, et al. Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir Med. 2016; 4(4):259-71.
[20] Scicluna BP, van Vught LA, Zwinderman AH, Wiewel MA, Davenport EE, Burnham KL, et al. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. Lancet Respir Med. 2017; 5(10):816-26.
[21] Seymour CW, Kennedy JN, Wang S, Chang CH, Elliott CF, Xu Z, et al. Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis. JAMA. 2019; 321(20):2003-17.
[22] Rumienczyk I, Kulecka M, Statkiewicz M, Ostrowski J, Mikula M. Oncology Drug Repurposing for Sepsis Treatment. Biomedicines. 2022;10(4):921.
[23] Reyes M, Filbin MR, Bhattacharyya RP, Billman K, Eisenhaure T, Hung DT, et al. An immune-cell signature of bacterial sepsis. Nat Med. 2020; 26(3):333-40.
[24] Beudeker CR, Vijlbrief DC, van Montfrans JM, Rooijakkers SHM, van der Flier M. Neonatal sepsis and transient immunodeficiency: Potential for novel immunoglobulin therapies? Front Immunol. 2022;13:1016877.
[25] Sun X, Wu J, Liu L, Chen Y, Tang Y, Liu S, et al. Transcriptional switch of hepatocytes initiates macrophage recruitment and T-cell suppression in endotoxemia. J Hepatol. 2022;77(2):436-452.
[26] Bjerkhaug AU, Granslo HN, Klingenberg C. Metabolic responses in neonatal sepsis-A systematic review of human metabolomic studies. Acta Paediatr. 2021;110(8):2316-2325.
[27] Liu PP, Yu XY, Pan QQ, Ren JJ, Han YX, Zhang K, et al. Multi-Omics and Network-Based Drug Repurposing for Septic Cardiomyopathy. Pharmaceuticals (Basel). 2025;18(1):43.
[28] Zheng LY, Duan Y, He PY, Wu MY, Wei ST, Du XH, et al. Dysregulated dendritic cells in sepsis: functional impairment and regulated cell death. Cell Mol Biol Lett. 2024;29(1):81.
[29] Antonopoulou A, Giamarellos-Bourboulis EJ. Immunomodulation in sepsis: state of the art and future perspective. Immunotherapy. 2011; 3(1):117-28.
[30] Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013; 369(21):2069.
[2] Shankar-Hari M, Rubenfeld GD. Understanding Long-Term Outcomes Following Sepsis: Implications and Challenges. Curr Infect Dis Rep. 2016; 18(11):37.
[3] Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL. Sepsis and septic shock. Nat Rev Dis Primers. 2016; 2:16045.
[4] Venet F, Monneret G. Advances in the understanding and treatment of sepsis-induced immunosuppression. Nat Rev Nephrol. 2018; 14(2):121-37.
[5] van der Poll T, Shankar-Hari M, Wiersinga WJ. The immunology of sepsis. Immunity. 2021; 54(11):2450-64.
[6] Deutschman CS, Tracey KJ. Sepsis: current dogma and new perspectives. Immunity. 2014; 40(4):463-75.
[7] Liu D, Huang SY, Sun JH, Zhang HC, Cai QL, Gao C, et al. Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options. Mil Med Res. 2022; 9(1):56.
[8] Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. 2020; 383(23):2255-73.
[9] Iba T, Maier CL, Helms J, Ferrer R, Thachil J, Levy JH. Managing sepsis and septic shock in an endothelial glycocalyx-friendly way: from the viewpoint of surviving sepsis campaign guidelines. Ann Intensive Care. 2024; 14(1):64.
[10] Schmidt EP, Yang Y, Janssen WJ, Gandjeva A, Perez MJ, Barthel L, et al. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med. 2012; 18(8):1217-23.
[11] Ostrowski SR, Sørensen AM, Windeløv NA, Perner A, Welling KL, Wanscher M, et al. High levels of soluble VEGF receptor 1 early after trauma are associated with shock, sympathoadrenal activation, glycocalyx degradation and inflammation in severely injured patients: a prospective study. Scand J Trauma Resusc Emerg Med. 2012; 20:27.
[12] Rizzo AN, Schmidt EP. The role of the alveolar epithelial glycocalyx in acute respiratory distress syndrome. Am J Physiol Cell Physiol. 2023; 324(4):C799-C806.
[13] Denning NL, Aziz M, Gurien SD, Wang P. DAMPs and NETs in Sepsis. Front Immunol. 2019; 10:2536.
[14] Fang J, Ding H, Huang J, Liu W, Hong T, Yang J, et al. Mac-1 blockade impedes adhesion-dependent neutrophil extracellular trap formation and ameliorates lung injury in LPS-induced sepsis. Front Immunol. 2025; 16:1548913.
[15] Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol. 2007; 5(8):577-82.
[16] van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. 2017; 17(7):407-20.
[17] Hotchkiss RS, Colston E, Yende S, Crouser ED, Martin GS, Albertson T, et al. Immune checkpoint inhibition in sepsis: a Phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab. Intensive Care Med. 2019;45(10):1360-1371.
[18] Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011; 306(23):2594-605.
[19] Davenport EE, Burnham KL, Radhakrishnan J, Humburg P, Hutton P, Mills TC, et al. Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir Med. 2016; 4(4):259-71.
[20] Scicluna BP, van Vught LA, Zwinderman AH, Wiewel MA, Davenport EE, Burnham KL, et al. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. Lancet Respir Med. 2017; 5(10):816-26.
[21] Seymour CW, Kennedy JN, Wang S, Chang CH, Elliott CF, Xu Z, et al. Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis. JAMA. 2019; 321(20):2003-17.
[22] Rumienczyk I, Kulecka M, Statkiewicz M, Ostrowski J, Mikula M. Oncology Drug Repurposing for Sepsis Treatment. Biomedicines. 2022;10(4):921.
[23] Reyes M, Filbin MR, Bhattacharyya RP, Billman K, Eisenhaure T, Hung DT, et al. An immune-cell signature of bacterial sepsis. Nat Med. 2020; 26(3):333-40.
[24] Beudeker CR, Vijlbrief DC, van Montfrans JM, Rooijakkers SHM, van der Flier M. Neonatal sepsis and transient immunodeficiency: Potential for novel immunoglobulin therapies? Front Immunol. 2022;13:1016877.
[25] Sun X, Wu J, Liu L, Chen Y, Tang Y, Liu S, et al. Transcriptional switch of hepatocytes initiates macrophage recruitment and T-cell suppression in endotoxemia. J Hepatol. 2022;77(2):436-452.
[26] Bjerkhaug AU, Granslo HN, Klingenberg C. Metabolic responses in neonatal sepsis-A systematic review of human metabolomic studies. Acta Paediatr. 2021;110(8):2316-2325.
[27] Liu PP, Yu XY, Pan QQ, Ren JJ, Han YX, Zhang K, et al. Multi-Omics and Network-Based Drug Repurposing for Septic Cardiomyopathy. Pharmaceuticals (Basel). 2025;18(1):43.
[28] Zheng LY, Duan Y, He PY, Wu MY, Wei ST, Du XH, et al. Dysregulated dendritic cells in sepsis: functional impairment and regulated cell death. Cell Mol Biol Lett. 2024;29(1):81.
[29] Antonopoulou A, Giamarellos-Bourboulis EJ. Immunomodulation in sepsis: state of the art and future perspective. Immunotherapy. 2011; 3(1):117-28.
[30] Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013; 369(21):2069.
| Files | ||
| Issue | Vol 12 No 1 (2026): Jan-Feb |
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| Section | Review Article(s) | |
| Keywords | ||
| Sepsis Inflammation Endothelium Oxidative stress Platelet adhesion | ||
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How to Cite
1.
Sanatkar M. The Immunological Landscape of Sepsis: From Cytokine Storm to Immune Paralysis. Arch Anesth & Crit Care. 2025;12(1):67-70.
