Semin Respir Crit Care Med
DOI: 10.1055/s-0044-1787554
Sebastiaan C.M. Joosten
1
Centre for Experimental and Molecular Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands
,
Willem J. Wiersinga
1
Centre for Experimental and Molecular Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands
2
Division of Infectious Diseases, Amsterdam University Medical Center, Amsterdam, The Netherlands
,
Tom van der Poll
1
Centre for Experimental and Molecular Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands
2
Division of Infectious Diseases, Amsterdam University Medical Center, Amsterdam, The Netherlands
› Author Affiliations
Funding S.C.M.J. is supported by a grant from The Dutch Ministery of Economic Affairs & Health Holland, TKI-program Life Sciences & Health (project DETECT-SEPSIS).
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Abstract
Sepsis stands as a prominent contributor to sickness and death on a global scale. The most current consensus definition characterizes sepsis as a life-threatening organ dysfunction stemming from an imbalanced host response to infection. This definition does not capture the intricate array of immune processes at play in sepsis, marked by simultaneous states of heightened inflammation and immune suppression. This overview delves into the immune-related processes of sepsis, elaborating about mechanisms involved in hyperinflammation and immune suppression. Moreover, we discuss stratification of patients with sepsis based on their immune profiles and how this could impact future sepsis management.
Keywords
sepsis -
review -
pathophysiology -
immune dysregulation -
host response
Publication History
Article published online:
01 July 2024
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References
1
Rudd KE,
Johnson SC,
Agesa KM.
et al.
Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet 2020; 395 (10219): 200-211
2
Wiersinga WJ,
van der Poll T.
Immunopathophysiology of human sepsis. EBioMedicine 2022; 86: 104363
3
Mantovani A,
Garlanda C.
Humoral innate immunity and acute-phase proteins. N Engl J Med 2023; 388 (05) 439-452
4
Wiersinga WJ,
Leopold SJ,
Cranendonk DR,
van der Poll T.
Host innate immune responses to sepsis. Virulence 2014; 5 (01) 36-44
5
Rock FL,
Hardiman G,
Timans JC,
Kastelein RA,
Bazan JF.
A family of human receptors structurally related to Drosophila toll. Proc Natl Acad Sci U S A 1998; 95 (02) 588-593
6
Murphy K,
Weaver C,
Berg J.
Janeway's Immunobiology. Vol 10. New York, NY:: Garland Science;; 2022
7
van der Poll T,
Opal SM.
Host-pathogen interactions in sepsis. Lancet Infect Dis 2008; 8 (01) 32-43
8
Chan JK,
Roth J,
Oppenheim JJ.
et al.
Alarmins: awaiting a clinical response. J Clin Invest 2012; 122 (08) 2711-2719
9
Opal SM,
Laterre PF,
Francois B.
et al;
ACCESS Study Group.
Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 2013; 309 (11) 1154-1162
10
Prantner D,
Nallar S,
Vogel SN.
The role of RAGE in host pathology and crosstalk between RAGE and TLR4 in innate immune signal transduction pathways. FASEB J 2020; 34 (12) 15659-15674
11
Yan Z,
Luo H,
Xie B.
et al.
Targeting adaptor protein SLP76 of RAGE as a therapeutic approach for lethal sepsis. Nat Commun 2021; 12 (01) 308
12
Siskind S,
Brenner M,
Wang P.
TREM-1 modulation strategies for sepsis. Front Immunol 2022; 13: 907387
13
François B,
Lambden S,
Fivez T.
et al;
ASTONISH investigators.
Prospective evaluation of the efficacy, safety, and optimal biomarker enrichment strategy for nangibotide, a TREM-1 inhibitor, in patients with septic shock (ASTONISH): a double-blind, randomised, controlled, phase 2b trial. Lancet Respir Med 2023; 11 (10) 894-904
14
Schulte W,
Bernhagen J,
Bucala R.
Cytokines in sepsis: potent immunoregulators and potential therapeutic targets–an updated view. Mediators Inflamm 2013; 2013: 165974
15
Li LL,
Dai B,
Sun YH,
Zhang TT.
The activation of IL-17 signaling pathway promotes pyroptosis in pneumonia-induced sepsis. Ann Transl Med 2020; 8 (11) 674-674
16
Denning NL,
Aziz M,
Gurien SD,
Wang P.
DAMPs and NETs in sepsis. Front Immunol 2019; 10: 2536
17
Jin H,
Aziz M,
Murao A.
et al.
Antigen-presenting aged neutrophils induce CD4+ T cells to exacerbate inflammation in sepsis. J Clin Invest 2023; 133 (14) e164585
18
Chen Z,
Zhang H,
Qu M.
et al.
Review: the emerging role of neutrophil extracellular traps in sepsis and sepsis-associated thrombosis. Front Cell Infect Microbiol 2021; 11: 653228
19
Castanheira FVS,
Kubes P.
Neutrophils and NETs in modulating acute and chronic inflammation. Blood 2019; 133 (20) 2178-2185
20
Wang L,
Zhou X,
Yin Y,
Mai Y,
Wang D,
Zhang X.
Hyperglycemia induces neutrophil extracellular traps formation through an NADPH oxidase-dependent pathway in diabetic retinopathy. Front Immunol 2019; 9 (JAN): 3076
21
Kolaczkowska E.
The older the faster: aged neutrophils in inflammation. Blood 2016; 128 (19) 2280-2282
22
Weng W,
Hu Z,
Pan Y.
Macrophage extracellular traps: current opinions and the state of research regarding various diseases. J Immunol Res 2022; 2022: 7050807
23
Delabranche X,
Stiel L,
Severac F.
et al.
Evidence of netosis in septic shock-induced disseminated intravascular coagulation. Shock 2017; 47 (03) 313-317
24
Sahu SK,
Kulkarni DH,
Ozanturk AN,
Ma L,
Kulkarni HS.
Emerging roles of the complement system in host-pathogen interactions. Trends Microbiol 2022; 30 (04) 390-402
25
Abe T,
Kubo K,
Izumoto S.
et al.
Complement activation in human sepsis is related to sepsis-induced disseminated intravascular coagulation. Shock 2020; 54 (02) 198-204
26
de Nooijer AH,
Kotsaki A,
Kranidioti E.
et al.
Complement activation in severely ill patients with sepsis: no relationship with inflammation and disease severity. Crit Care 2023; 27 (01) 63
27
de Jong HK,
van der Poll T,
Wiersinga WJ.
The systemic pro-inflammatory response in sepsis. J Innate Immun 2010; 2 (05) 422-430
28
Sommerfeld O,
Medyukhina A,
Neugebauer S.
et al.
Targeting complement C5a receptor 1 for the treatment of immunosuppression in sepsis. Mol Ther 2021; 29 (01) 338-346
29
Levi M,
van der Poll T.
Coagulation and sepsis. Thromb Res 2017; 149: 38-44
30
Iba T,
Watanabe E,
Umemura Y.
et al;
Japanese Surviving Sepsis Campaign Guideline Working Group for disseminated intravascular coagulation.
Sepsis-associated disseminated intravascular coagulation and its differential diagnoses. J Intensive Care 2019; 7 (01) 32
31
Levi M,
Ten Cate H.
Disseminated intravascular coagulation. N Engl J Med 1999; 341 (08) 586-592
32
Osterud B,
Flaegstad T.
Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavourable prognosis. Thromb Haemost 1983; 49 (01) 5-7
33
Taylor FB,
Chang ACK,
Peer G,
Li A,
Ezban M,
Hedner U.
Active site inhibited factor VIIa (DEGR VIIa) attenuates the coagulant and interleukin-6 and -8, but not tumor necrosis factor, responses of the baboon to LD100 Escherichia coli
. Blood 1998; 91 (05) 1609-1615
34
de Stoppelaar SF,
van 't Veer C,
van der Poll T.
The role of platelets in sepsis. Thromb Haemost 2014; 112 (04) 666-677
35
Hoshino K,
Nakashio M,
Maruyama J,
Irie Y,
Kawano Y,
Ishikura H.
Validating plasminogen activator inhibitor-1 as a poor prognostic factor in sepsis. Acute Med Surg 2020; 7 (01) e581
36
Engelmann B,
Massberg S.
Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
37
Kimball AS,
Obi AT,
Diaz JA,
Henke PK.
The emerging role of NETs in venousthrombosis and immunothrombosis. Front Immunol 2016; 7: 236
38
McDonald B,
Davis RP,
Kim SJ.
et al.
Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. Blood 2017; 129 (10) 1357-1367
39
Keragala CB,
Draxler DF,
McQuilten ZK,
Medcalf RL.
Haemostasis and innate immunity - a complementary relationship: a review of the intricate relationship between coagulation and complement pathways. Br J Haematol 2018; 180 (06) 782-798
40
Silasi-Mansat R,
Zhu H,
Popescu NI.
et al.
Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood 2010; 116 (06) 1002-1010
41
Wu C,
Lu W,
Zhang Y.
et al.
Inflammasome activation triggers blood clotting and host death through pyroptosis. Immunity 2019; 50 (06) 1401-1411.e4
42
Walton AH,
Muenzer JT,
Rasche D.
et al.
Reactivation of multiple viruses in patients with sepsis. PLoS One 2014; 9 (02) e98819
43
Limaye AP,
Kirby KA,
Rubenfeld GD.
et al.
Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 2008; 300 (04) 413-422
44
Torres LK,
Pickkers P,
van der Poll T.
Sepsis-induced immunosuppression. Annu Rev Physiol 2022; 84: 157-181
45
Finfer S,
Venkatesh B,
Hotchkiss RS,
Sasson SC.
Lymphopenia in sepsis-an acquired immunodeficiency?. Immunol Cell Biol 2023; 101 (06) 535-544
46
Hohlstein P,
Gussen H,
Bartneck M.
et al.
Prognostic relevance of altered lymphocyte subpopulations in critical illness and sepsis. J Clin Med 2019; 8 (03) 353
47
Boomer JS,
To K,
Chang KC.
et al.
Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 2011; 306 (23) 2594-2605
48
Hotchkiss RS,
Monneret G,
Payen D.
Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 2013; 13 (12) 862-874
49
Wherry EJ,
Kurachi M.
Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 2015; 15 (08) 486-499
50
Guignant C,
Lepape A,
Huang X.
et al.
Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit Care 2011; 15 (02) R99
51
Hotchkiss RS,
Colston E,
Yende S.
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
52
Watanabe E,
Nishida O,
Kakihana Y.
et al.
Pharmacokinetics, pharmacodynamics, and safety of nivolumab in patients with sepsis-induced immunosuppression: a multicenter, open-label phase 1/2 study. Shock 2020; 53 (06) 686-694
53
Biswas SK,
Lopez-Collazo E.
Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol 2009; 30 (10) 475-487
54
Venet F,
Lukaszewicz AC,
Payen D,
Hotchkiss R,
Monneret G.
Monitoring the immune response in sepsis: a rational approach to administration of immunoadjuvant therapies. Curr Opin Immunol 2013; 25 (04) 477-483
55
Foster SL,
Hargreaves DC,
Medzhitov R.
Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 2007; 447 (7147) 972-978
56
Naik S,
Fuchs E.
Inflammatory memory and tissue adaptation in sickness and in health. Nature 2022; 607 (7918) 249-255
57
Gao YL,
Yao Y,
Zhang X.
et al.
Regulatory T cells: angels or demons in the pathophysiology of sepsis?. Front Immunol 2022; 13: 829210
58
Xu J,
Li J,
Xiao K.
et al.
Dynamic changes in human HLA-DRA gene expression and Th cell subsets in sepsis: indications of immunosuppression and associated outcomes. Scand J Immunol 2020; 91 (01) e12813
59
Ost M,
Singh A,
Peschel A,
Mehling R,
Rieber N,
Hartl D.
Myeloid-derived suppressor cells in bacterial infections. Front Cell Infect Microbiol 2016; 6: 37
60
Reyes M,
Filbin MR,
Bhattacharyya RP.
et al.
An immune-cell signature of bacterial sepsis. Nat Med 2020; 26 (03) 333-340
61
Kwok AJ,
Allcock A,
Ferreira RC.
et al;
Emergency Medicine Research Oxford (EMROx).
Neutrophils and emergency granulopoiesis drive immune suppression and an extreme response endotype during sepsis. Nat Immunol 2023; 24 (05) 767-779
62
O'Neill LA,
Kishton RJ,
Rathmell J.
A guide to immunometabolism for immunologists. Nat Rev Immunol 2016; 16 (09) 553-565
63
Liu W,
Liu T,
Zheng Y,
Xia Z.
Metabolic reprogramming and its regulatory mechanism in sepsis-mediated inflammation. J Inflamm Res 2023; 16: 1195-1207
64
Awasthi D,
Nagarkoti S,
Sadaf S,
Chandra T,
Kumar S,
Dikshit M.
Glycolysis dependent lactate formation in neutrophils: a metabolic link between NOX-dependent and independent NETosis. Biochim Biophys Acta Mol Basis Dis 2019; 1865 (12) 165542
65
Shao C,
Lin S,
Liu S.
et al.
HIF1α-induced glycolysis in macrophage is essential for the protective effect of ouabain during endotoxemia. Oxid Med Cell Longev 2019
66
Kelly B,
O'Neill LAJ.
Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res 2015; 25 (07) 771-784
67
Liu TF,
Vachharajani VT,
Yoza BK,
McCall CE.
NAD+-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response. J Biol Chem 2012; 287 (31) 25758-25769
68
Zhou HC,
Yu WW,
Yan XY.
et al.
Lactate-driven macrophage polarization in the inflammatory microenvironment alleviates intestinal inflammation. Front Immunol 2022; 13: 1013686
69
Yang K,
Xu J,
Fan M.
et al.
Lactate suppresses macrophage pro-inflammatory response to LPS stimulation by inhibition of YAP and NF-κB activation via GPR81-mediated signaling. Front Immunol 2020; 11 DOI:
10.3389/fimmu.2020.587913.
70
Ivashkiv LB.
The hypoxia-lactate axis tempers inflammation. Nat Rev Immunol 2020; 20 (02) 85-86
71
Cheng SC,
Scicluna BP,
Arts RJW.
et al.
Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat Immunol 2016; 17 (04) 406-413
72
Kraft BD,
Chen L,
Suliman HB,
Piantadosi CA,
Welty-Wolf KE.
Peripheral blood mononuclear cells demonstrate mitochondrial damage clearance during sepsis. Crit Care Med 2019; 47 (05) 651-658
73
Venet F,
Demaret J,
Blaise BJ.
et al.
IL-7 restores T lymphocyte immunometabolic failure in septic shock patients through mTOR activation. J Immunol 2017; 199 (05) 1606-1615
74
Bekkering S,
Domínguez-Andrés J,
Joosten LAB,
Riksen NP,
Netea MG.
Trained immunity: reprogramming innate immunity in health and disease. Annu Rev Immunol 2021; 39: 667-693
75
Netea MG,
Joosten LAB,
Latz E.
et al.
Trained immunity: a program of innate immune memory in health and disease. Science 2016; 352 (6284) aaf1098
76
Ifrim DC,
Quintin J,
Joosten LAB.
et al.
Trained immunity or tolerance: opposing functional programs induced in human monocytes after engagement of various pattern recognition receptors. Clin Vaccine Immunol 2014; 21 (04) 534-545
77
Cheng SC,
Quintin J,
Cramer RA.
et al.
mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 2014; 345 (6204) 1250684
78
Arts RJW,
Carvalho A,
La Rocca C.
et al.
Immunometabolic pathways in BCG-induced trained immunity. Cell Rep 2016; 17 (10) 2562-2571
79
Arts RJW,
Novakovic B,
Ter Horst R.
et al.
Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab 2016; 24 (06) 807-819
80
Bomans K,
Schenz J,
Sztwiertnia I,
Schaack D,
Weigand MA,
Uhle F.
Sepsis induces a long-lasting state of trained immunity in bone marrow monocytes. Front Immunol 2018; 9 (NOV): 2685
81
Giamarellos-Bourboulis EJ,
Tsilika M,
Moorlag S.
et al.
Activate: randomized clinical trial of BCG vaccination against infection in the elderly. Cell 2020; 183 (02) 315-323.e9
82
Koekenbier EL,
Fohse K,
van de Maat JS.
et al;
BCG-PRIME study group.
Bacillus Calmette-Guérin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbidities: a randomized controlled trial. Clin Microbiol Infect 2023; 29 (06) 781-788
83
Pittet LF,
Messina NL,
Orsini F.
et al;
BRACE Trial Consortium Group.
Randomized trial of BCG vaccine to protect against Covid-19 in health care workers. N Engl J Med 2023; 388 (17) 1582-1596
84
Schrijver DP,
Röring RJ,
Deckers J.
et al.
Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells. Nat Biomed Eng 2023; 7 (09) 1097-1112
85
Davenport EE,
Burnham KL,
Radhakrishnan J.
et al.
Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir Med 2016; 4 (04) 259-271
86
Antcliffe DB,
Burnham KL,
Al-Beidh F.
et al.
Transcriptomic signatures in sepsis and a differential response to steroids. From the VANISH randomized trial. Am J Respir Crit Care Med 2019; 199 (08) 980-986
87
Cano-Gamez E,
Burnham KL,
Goh C.
et al;
GAinS Investigators.
An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression. Sci Transl Med 2022; 14 (669) eabq4433
88
Scicluna BP,
van Vught LA,
Zwinderman AH.
et al;
MARS consortium.
Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. Lancet Respir Med 2017; 5 (10) 816-826
89
Sweeney TE,
Azad TD,
Donato M.
et al.
Unsupervised analysis of transcriptomics in bacterial sepsis across multiple datasets reveals three robust clusters. Crit Care Med 2018; 46 (06) 915-925
90
Matthay MA,
Zemans RL,
Zimmerman GA.
et al.
Acute respiratory distress syndrome. Nat Rev Dis Prim 2019; 5 (01) 915
91
Sinha P,
Kerchberger VE,
Willmore A.
et al.
Identifying molecular phenotypes in sepsis: an analysis of two prospective observational cohorts and secondary analysis of two randomised controlled trials. Lancet Respir Med 2023; 11 (11) 965-974
92
Schuurman AR,
Sloot PMA,
Wiersinga WJ,
van der Poll T.
Embracing complexity in sepsis. Crit Care 2023; 27 (01) 102
93
Schuurman AR,
Reijnders TDY,
Kullberg RFJ,
Butler JM,
van der Poll T,
Wiersinga WJ.
Sepsis: deriving biological meaning and clinical applications from high-dimensional data. Intensive Care Med Exp 2021; 9 (01) 27
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