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Inflammation Research
Published in: Inflammation Research 11/2016

01-11-2016 | Review

Role of cellular events in the pathophysiology of sepsis

Authors: Chandra Bhan, Pankaj Dipankar, Papiya Chakraborty, Pranita P. Sarangi

Published in: Inflammation Research | Issue 11/2016

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Abstract

Introduction

Sepsis is a dysregulated host immune response due to an uncontrolled infection. It is a leading cause of mortality in adult intensive care units globally. When the host immune response induced against a local infection fails to contain it locally, it progresses to sepsis, severe sepsis, septic shock and death.

Method

Literature survey was performed on the roles of different innate and adaptive immune cells in the development and progression of sepsis. Additionally, the effects of septic changes on reprogramming of different immune cells were also summarized to prepare the manuscript.

Findings

Scientific evidences to date suggest that the loss of balance between inflammatory and anti-inflammatory responses results in reprogramming of immune cell activities that lead to irreversible tissue damaging events and multi-organ failure during sepsis. Many surface receptors expressed on immune cells at various stages of sepsis have been suggested as biomarkers for sepsis diagnosis. Various immunomodulatory therapeutics, which could improve the functions of immune cells during sepsis, were shown to restore immunological homeostasis and improve survival in animal models of sepsis.

Conclusion

In-depth and comprehensive knowledge on the immune cell activities and their correlation with severity of sepsis will help clinicians and scientists to design effective immunomodulatory therapeutics for treating sepsis.
Literature
1.
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315:801–10.PubMedPubMedCentralCrossRef
2.
3.
4.
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–10.PubMedCrossRef
5.
6.
7.
Beale R, Reinhart K, Brunkhorst FM, Dobb G, Levy M, Martin G, et al. Promoting global research excellence in severe sepsis (PROGRESS): lessons from an international sepsis registry. Infection. 2009;37:222–32.PubMedCrossRef
8.
9.
10.
11.
Balajthy Z, Aradi J, Balajthy Z. Molecular therapies. Debrecen: Debreceni Egyetem; 2011. p. 51–8.
12.
13.
Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138–50.PubMedCrossRef
14.
Moore FA, Sauaia A, Moore EE, Haenel JB, Burch JM, Lezotte DC. Postinjury multiple organ failure: a bimodal phenomenon. J Trauma. 1996;40:501–10 (discussion 510–2).PubMedCrossRef
15.
16.
Lerman YV, Lim K, Hyun YM, Falkner KL, Yang H, Pietropaoli AP, et al. Sepsis lethality via exacerbated tissue infiltration and TLR-induced cytokine production by neutrophils is integrin alpha3beta1-dependent. Blood. 2014;124:3515–23.PubMedPubMedCentralCrossRef
17.
Sawa Y, Ueki T, Hata M, Iwasawa K, Tsuruga E, Kojima H, et al. LPS-induced IL-6, IL-8, VCAM-1, and ICAM-1 expression in human lymphatic endothelium. J Histochem Cytochem. 2008;56:97–109.PubMedPubMedCentralCrossRef
18.
Lerman YV, Kim M. Neutrophil migration under normal and sepsis conditions. Cardiovasc Hematol Disord: Drug Targets. 2015;15:19–28.CrossRef
19.
Zhang P, Xie M, Spitzer JA. Hepatic neutrophil sequestration in early sepsis: enhanced expression of adhesion molecules and phagocytic activity. Shock. 1994;2:133–40.PubMedCrossRef
20.
21.
Hoffmeyer F, Witte K, Schmidt RE. The high-affinity Fc gamma RI on PMN: regulation of expression and signal transduction. Immunology. 1997;92:544–52.PubMedPubMedCentralCrossRef
22.
Layseca-Espinosa E, Perez-Gonzalez LF, Torres-Montes A, Baranda L, de la Fuente H, Rosenstein Y, et al. Expression of CD64 as a potential marker of neonatal sepsis. Pediatr Allergy Immunol. 2002;13:319–27.PubMedCrossRef
23.
McAvoy EF, McDonald B, Parsons SA, Wong CH, Landmann R, Kubes P. The role of CD14 in neutrophil recruitment within the liver microcirculation during endotoxemia. J Immunol. 2011;186:2592–601.PubMedCrossRef
24.
25.
Cristofaro P, Opal SM. The Toll-like receptors and their role in septic shock. Expert Opin Ther Targets. 2003;7:603–12.PubMedCrossRef
26.
Bouchon A, Facchetti F, Weigand MA, Colonna M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature. 2001;410:1103–7.PubMedCrossRef
27.
Oberholzer A, Oberholzer C, Moldawer LL. Sepsis syndromes: understanding the role of innate and acquired immunity. Shock. 2001;16:83–96.PubMedCrossRef
28.
Brown K, Brain S, Pearson J, Edgeworth J, Lewis S, Treacher D. Neutrophils in development of multiple organ failure in sepsis. Lancet. 2006;368:157–69.PubMedCrossRef
29.
Wagner C, Pioch M, Meyer C, Iking-Konert C, Andrassy K, Hansch GM. Differentiation of polymorphonuclear neutrophils in patients with systemic infections and chronic inflammatory diseases: evidence of prolonged life span and de novo synthesis of fibronectin. J Mol Med (Berl). 2000;78:337–45.CrossRef
30.
Taneja R, Parodo J, Jia SH, Kapus A, Rotstein OD, Marshall JC. Delayed neutrophil apoptosis in sepsis is associated with maintenance of mitochondrial transmembrane potential and reduced caspase-9 activity. Crit Care Med. 2004;32:1460–9.PubMedCrossRef
31.
Jia SH, Parodo J, Kapus A, Rotstein OD, Marshall JC. Dynamic regulation of neutrophil survival through tyrosine phosphorylation or dephosphorylation of caspase-8. J Biol Chem. 2008;283:5402–13.PubMedCrossRef
32.
33.
34.
Albertine KH, Soulier MF, Wang Z, Ishizaka A, Hashimoto S, Zimmerman GA, et al. Fas and fas ligand are up-regulated in pulmonary edema fluid and lung tissue of patients with acute lung injury and the acute respiratory distress syndrome. Am J Pathol. 2002;161:1783–96.PubMedPubMedCentralCrossRef
35.
Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–5.PubMedCrossRef
36.
Camicia G, Pozner R, de Larranaga G. Neutrophil extracellular traps in sepsis. Shock. 2014;42:286–94.PubMedCrossRef
37.
Gao X, Hao S, Yan H, Ding W, Li K, Li J. Neutrophil extracellular traps contribute to the intestine damage in endotoxemic rats. J Surg Res. 2015;195:211–8.PubMedCrossRef
38.
Hashiba M, Huq A, Tomino A, Hirakawa A, Hattori T, Miyabe H, et al. Neutrophil extracellular traps in patients with sepsis. J Surg Res. 2015;194:248–54.PubMedCrossRef
39.
40.
Schulte W, Bernhagen J, Bucala R. Cytokines in sepsis: potent immunoregulators and potential therapeutic targets—an updated view. Mediat Inflamm. 2013;2013:165974.CrossRef
41.
Kopydlowski KM, Salkowski CA, Cody MJ, van Rooijen N, Major J, Hamilton TA, et al. Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivo. J Immunol. 1999;163:1537–44.PubMed
42.
43.
Sha Y, Zmijewski J, Xu Z, Abraham E. HMGB1 develops enhanced proinflammatory activity by binding to cytokines. J Immunol. 2008;180:2531–7.PubMedCrossRef
44.
Wang H, Yang H, Tracey KJ. Extracellular role of HMGB1 in inflammation and sepsis. J Intern Med. 2004;255:320–31.PubMedCrossRef
45.
Yu M, Wang H, Ding A, Golenbock DT, Latz E, Czura CJ, et al. HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock. 2006;26:174–9.PubMedCrossRef
46.
Huang X, Chen Y, Chung CS, Yuan Z, Monaghan SF, Wang F, et al. Identification of B7-H1 as a novel mediator of the innate immune/proinflammatory response as well as a possible myeloid cell prognostic biomarker in sepsis. J Immunol. 2014;192:1091–9.PubMedCrossRef
47.
Riedemann NC, Guo RF, Gao H, Sun L, Hoesel M, Hollmann TJ, et al. Regulatory role of C5a on macrophage migration inhibitory factor release from neutrophils. J Immunol. 2004;173:1355–9.PubMedCrossRef
48.
49.
Ellaban E, Bolgos G, Remick D. Selective macrophage suppression during sepsis. Cell Immunol. 2004;231:103–11.PubMedCrossRef
50.
51.
Bergenfelz C, Medrek C, Ekstrom E, Jirstrom K, Janols H, Wullt M, et al. Wnt5a induces a tolerogenic phenotype of macrophages in sepsis and breast cancer patients. J Immunol. 2012;188:5448–58.PubMedCrossRef
52.
Mahajan S, Saini A, Chandra V, Nanduri R, Kalra R, Bhagyaraj E, et al. Nuclear receptor Nr4a2 promotes alternative polarization of macrophages and confer protection in sepsis. J Biol Chem. 2015;290(30):18304–14.PubMedPubMedCentralCrossRef
53.
Newton S, Ding Y, Chung CS, Chen Y, Lomas-Neira JL, Ayala A. Sepsis-induced changes in macrophage co-stimulatory molecule expression: CD86 as a regulator of anti-inflammatory IL-10 response. Surg Infect (Larchmt). 2004;5:375–83.CrossRef
54.
Dahdah A, Gautier G, Attout T, Fiore F, Lebourdais E, Msallam R, et al. Mast cells aggravate sepsis by inhibiting peritoneal macrophage phagocytosis. J Clin Invest. 2014;124:4577–89.PubMedPubMedCentralCrossRef
55.
Scumpia PO, McAuliffe PF, O’Malley KA, Ungaro R, Uchida T, Matsumoto T, et al. CD11c + dendritic cells are required for survival in murine polymicrobial sepsis. J Immunol. 2005;175:3282–6.PubMedCrossRef
56.
Wen H, Hogaboam CM, Gauldie J, Kunkel SL. Severe sepsis exacerbates cell-mediated immunity in the lung due to an altered dendritic cell cytokine profile. Am J Pathol. 2006;168:1940–50.PubMedPubMedCentralCrossRef
57.
Dreschler K, Bratke K, Petermann S, Thamm P, Kuepper M, Virchow JC, et al. Altered phenotype of blood dendritic cells in patients with acute pneumonia. Respiration. 2012;83:209–17.PubMedCrossRef
58.
Hotchkiss RS, Tinsley KW, Swanson PE, Grayson MH, Osborne DF, Wagner TH, et al. Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol. 2002;168:2493–500.PubMedCrossRef
59.
Guisset O, Dilhuydy MS, Thiebaut R, Lefevre J, Camou F, Sarrat A, et al. Decrease in circulating dendritic cells predicts fatal outcome in septic shock. Intensive Care Med. 2007;33:148–52.PubMedCrossRef
60.
Bohannon J, Cui W, Sherwood E, Toliver-Kinsky T. Dendritic cell modification of neutrophil responses to infection after burn injury. J Immunol. 2010;185:2847–53.PubMedPubMedCentralCrossRef
61.
Pène F, Courtine E, Ouaaz F, Zuber B, Sauneuf B, Sirgo G, et al. Toll-like receptors 2 and 4 contribute to sepsis-induced depletion of spleen dendritic cells. Infect Immun. 2009;77:5651–8.PubMedPubMedCentralCrossRef
62.
Poehlmann H, Schefold JC, Zuckermann-Becker H, Volk HD, Meisel C. Phenotype changes and impaired function of dendritic cell subsets in patients with sepsis: a prospective observational analysis. Crit Care. 2009;13:R119.PubMedPubMedCentralCrossRef
63.
Faivre V, Lukaszewicz AC, Alves A, Charron D, Payen D, Haziot A. Human monocytes differentiate into dendritic cells subsets that induce anergic and regulatory T cells in sepsis. PLoS ONE. 2012;7:e47209.PubMedPubMedCentralCrossRef
64.
Gautier EL, Huby T, Saint-Charles F, Ouzilleau B, Chapman MJ, Lesnik P. Enhanced dendritic cell survival attenuates lipopolysaccharide-induced immunosuppression and increases resistance to lethal endotoxic shock. J Immunol. 2008;180:6941–6.PubMedCrossRef
65.
Wesche-Soldato DE, Chung CS, Lomas-Neira J, Doughty LA, Gregory SH, Ayala A. In vivo delivery of caspase-8 or Fas siRNA improves the survival of septic mice. Blood. 2005;106:2295–301.PubMedPubMedCentralCrossRef
66.
67.
Sherwood ER, Enoh VT, Murphey ED, Lin CY. Mice depleted of CD8 + T and NK cells are resistant to injury caused by cecal ligation and puncture. Lab Invest. 2004;84:1655–65.PubMedCrossRef
68.
Badgwell B, Parihar R, Magro C, Dierksheide J, Russo T, Carson WE 3rd. Natural killer cells contribute to the lethality of a murine model of Escherichia coli infection. Surgery. 2002;132:205–12.PubMedCrossRef
69.
Hotchkiss RS, Tinsley KW, Swanson PE, Schmieg RE Jr, Hui JJ, Chang KC, et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4 + T lymphocytes in humans. J Immunol. 2001;166:6952–63.PubMedCrossRef
70.
Zeerleder S, Hack CE, Caliezi C, van Mierlo G, Eerenberg-Belmer A, Wolbink A, et al. Activated cytotoxic T cells and NK cells in severe sepsis and septic shock and their role in multiple organ dysfunction. Clin Immunol. 2005;116:158–65.PubMedCrossRef
71.
Perona-Wright G, Mohrs K, Szaba FM, Kummer LW, Madan R, Karp CL, et al. Systemic but not local infections elicit immunosuppressive IL-10 production by natural killer cells. Cell Host Microbe. 2009;6:503–12.PubMedPubMedCentralCrossRef
72.
Kuijpers TW, Baars PA, Dantin C, van den Burg M, van Lier RA, Roosnek E. Human NK cells can control CMV infection in the absence of T cells. Blood. 2008;112:914–5.PubMedCrossRef
73.
Delano MJ, Thayer T, Gabrilovich S, Kelly-Scumpia KM, Winfield RD, Scumpia PO, et al. Sepsis induces early alterations in innate immunity that impact mortality to secondary infection. J Immunol. 2011;186:195–202.PubMedCrossRef
74.
Bour-Jordan H, Esensten JH, Martinez-Llordella M, Penaranda C, Stumpf M, Bluestone JA. Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/B7 family. Immunol Rev. 2011;241:180–205.PubMedPubMedCentralCrossRef
75.
De AK, Kodys KM, Pellegrini J, Yeh B, Furse RK, Bankey P, et al. Induction of global anergy rather than inhibitory Th2 lymphokines mediates posttrauma T cell immunodepression. Clin Immunol. 2000;96:52–66.PubMedCrossRef
76.
Roth G, Moser B, Krenn C, Brunner M, Haisjackl M, Almer G, et al. Susceptibility to programmed cell death in T-lymphocytes from septic patients: a mechanism for lymphopenia and Th2 predominance. Biochem Biophys Res Commun. 2003;308:840–6.PubMedCrossRef
77.
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;306:2594–605.PubMedPubMedCentralCrossRef
78.
Pachot A, Monneret G, Voirin N, Leissner P, Venet F, Bohe J, et al. Longitudinal study of cytokine and immune transcription factor mRNA expression in septic shock. Clin Immunol. 2005;114:61–9.PubMedCrossRef
79.
Carson WF, Cavassani KA, Ito T, Schaller M, Ishii M, Dou Y, et al. Impaired CD4 + T-cell proliferation and effector function correlates with repressive histone methylation events in a mouse model of severe sepsis. Eur J Immunol. 2010;40:998–1010.PubMedPubMedCentralCrossRef
80.
Cabrera-Perez J, Condotta SA, James BR, Kashem SW, Brincks EL, Rai D, et al. Alterations in antigen-specific naive CD4 T cell precursors after sepsis impairs their responsiveness to pathogen challenge. J Immunol. 2015;194:1609–20.PubMedPubMedCentralCrossRef
81.
Guignant C, Lepape A, Huang X, Kherouf H, Denis L, Poitevin F, et al. Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit Care. 2011;15:R99.PubMedPubMedCentralCrossRef
82.
Brahmamdam P, Inoue S, Unsinger J, Chang KC, McDunn JE, Hotchkiss RS. Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J Leukoc Biol. 2010;88:233–40.PubMedCrossRef
83.
Gurung P, Rai D, Condotta SA, Babcock JC, Badovinac VP, Griffith TS. Immune unresponsiveness to secondary heterologous bacterial infection after sepsis induction is TRAIL dependent. J Immunol. 2011;187:2148–54.PubMedPubMedCentralCrossRef
84.
Tupin E, Kinjo Y, Kronenberg M. The unique role of natural killer T cells in the response to microorganisms. Nat Rev Microbiol. 2007;5:405–17.PubMedCrossRef
85.
86.
Emoto M, Miyamoto M, Yoshizawa I, Emoto Y, Schaible UE, Kita E, et al. Critical role of NK cells rather than Vα14 + NKT cells in lipopolysaccharide-induced lethal shock in mice. J Immunol. 2002;169:1426–32.PubMedCrossRef
87.
Tsujimoto H, Ono S, Matsumoto A, Kawabata T, Kinoshita M, Majima T, et al. A critical role of CpG motifs in a murine peritonitis model by their binding to highly expressed toll-like receptor-9 on liver NKT cells. J Hepatol. 2006;45:836–43.PubMedCrossRef
88.
89.
Palmer JL, Tulley JM, Kovacs EJ, Gamelli RL, Taniguchi M, Faunce DE. Injury-induced suppression of effector T cell immunity requires CD1d-positive APCs and CD1d-restricted NKT cells. J Immunol. 2006;177:92–9.PubMedCrossRef
90.
Scott MJ, Hoth JJ, Turina M, Woods DR, Cheadle WG. Interleukin-10 suppresses natural killer cell but not natural killer T cell activation during bacterial infection. Cytokine. 2006;33:79–86.PubMedCrossRef
91.
Rhee RJ, Carlton S, Lomas JL, Lane C, Brossay L, Cioffi WG, et al. Inhibition of CD1d activation suppresses septic mortality: a role for NK-T cells in septic immune dysfunction. J Surg Res. 2003;115:74–81.PubMedCrossRef
92.
Li L, Huang L, Sun-sang JS, Lobo PI, Brown MG, Gregg RK, et al. NKT cell activation mediates neutrophil IFN-γ production and renal ischemia-reperfusion injury. J Immunol. 2007;178:5899–911.PubMedCrossRef
93.
Carding SR, Egan PJ. Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol. 2002;2:336–45.PubMedCrossRef
94.
Hedges JF, Lubick KJ, Jutila MA. Gamma delta T cells respond directly to pathogen-associated molecular patterns. J Immunol. 2005;174:6045–53.PubMedCrossRef
95.
Jameson J, Witherden D, Havran WL. T-cell effector mechanisms: gammadelta and CD1d-restricted subsets. Curr Opin Immunol. 2003;15:349–53.PubMedCrossRef
96.
Schwacha MG, Ayala A, Chaudry IH. Insights into the role of gammadelta T lymphocytes in the immunopathogenic response to thermal injury. J Leukoc Biol. 2000;67:644–50.PubMed
97.
Daniel T, Thobe BM, Chaudry IH, Choudhry MA, Hubbard WJ, Schwacha MG. Regulation of the postburn wound inflammatory response by gammadelta T-cells. Shock. 2007;28:278–83.PubMedCrossRef
98.
Alexander M, Daniel T, Chaudry IH, Choudhry MA, Schwacha MG. T cells of the gammadelta T-cell receptor lineage play an important role in the postburn wound healing process. J Burn Care Res. 2006;27:18–25.PubMedCrossRef
99.
100.
Chung CS, Watkins L, Funches A, Lomas-Neira J, Cioffi WG, Ayala A. Deficiency of gammadelta T lymphocytes contributes to mortality and immunosuppression in sepsis. Am J Physiol Regul Integr Comp Physiol. 2006;291:R1338–43.PubMedPubMedCentralCrossRef
101.
Enoh VT, Lin SH, Lin CY, Toliver-Kinsky T, Murphey ED, Varma TK, et al. Mice depleted of alphabeta but not gammadelta T cells are resistant to mortality caused by cecal ligation and puncture. Shock. 2007;27:507–19.PubMedCrossRef
102.
Matsushima A, Ogura H, Fujita K, Koh T, Tanaka H, Sumi Y, et al. Early activation of gammadelta T lymphocytes in patients with severe systemic inflammatory response syndrome. Shock. 2004;22:11–5.PubMedCrossRef
103.
Venet F, Bohe J, Debard AL, Bienvenu J, Lepape A, Monneret G. Both percentage of gammadelta T lymphocytes and CD3 expression are reduced during septic shock. Crit Care Med. 2005;33:2836–40.PubMedCrossRef
104.
Belkaid Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol. 2007;7:875–88.PubMedCrossRef
105.
MacConmara MP, Maung AA, Fujimi S, McKenna AM, Delisle A, Lapchak PH, et al. Increased CD4 + CD25 + T regulatory cell activity in trauma patients depresses protective Th1 immunity. Ann Surg. 2006;244:514–23.PubMedPubMedCentral
106.
Scumpia PO, Delano MJ, Kelly KM, O’Malley KA, Efron PA, McAuliffe PF, et al. Increased natural CD4 + CD25 + regulatory T cells and their suppressor activity do not contribute to mortality in murine polymicrobial sepsis. J Immunol. 2006;177:7943–9.PubMedCrossRef
107.
Wisnoski N, Chung CS, Chen Y, Huang X, Ayala A. The contribution of CD4 + CD25 + T-regulatory-cells to immune suppression in sepsis. Shock. 2007;27:251–7.PubMedPubMedCentralCrossRef
108.
Chen X, Baumel M, Mannel DN, Howard OM, Oppenheim JJ. Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4 + CD25 + T regulatory cells. J Immunol. 2007;179:154–61.PubMedCrossRef
109.
Wesche DE, Lomas-Neira JL, Perl M, Chung CS, Ayala A. Leukocyte apoptosis and its significance in sepsis and shock. J Leukoc Biol. 2005;78:325–37.PubMedCrossRef
110.
Tang L, Bai J, Chung CS, Lomas-Neira J, Chen Y, Huang X, et al. Programmed cell death receptor ligand 1 modulates the regulatory T cells’ capacity to repress shock/sepsis-induced indirect acute lung injury by recruiting phosphatase SRC homology region 2 domain-containing phosphatase 1. Shock. 2015;43:47–54.PubMedPubMedCentralCrossRef
111.
Molinaro R, Pecli C, Guilherme RF, Alves-Filho JC, Cunha FQ, Canetti C, et al. CCR4 controls the suppressive effects of regulatory T cells on early and late events during severe sepsis. PLoS ONE. 2015;10:e0133227.PubMedPubMedCentralCrossRef
112.
Bermejo-Martin JF, Andaluz-Ojeda D, Almansa R, Gandia F, Gomez-Herreras JI, Gomez-Sanchez E, et al. Defining immunological dysfunction in sepsis: a requisite tool for precision medicine. J Infect. 2016;72:525–36.PubMedCrossRef
113.
Ehrenstein MR, Notley CA. The importance of natural IgM: scavenger, protector and regulator. Nat Rev Immunol. 2010;10:778–86.PubMedCrossRef
114.
Quartier P, Potter PK, Ehrenstein MR, Walport MJ, Botto M. Predominant role of IgM-dependent activation of the classical pathway in the clearance of dying cells by murine bone marrow-derived macrophages in vitro. Eur J Immunol. 2005;35:252–60.PubMedCrossRef
115.
Kelly-Scumpia KM, Scumpia PO, Weinstein JS, Delano MJ, Cuenca AG, Nacionales DC, et al. B cells enhance early innate immune responses during bacterial sepsis. J Exp Med. 2011;208:1673–82.PubMedPubMedCentralCrossRef
116.
Rauch PJ, Chudnovskiy A, Robbins CS, Weber GF, Etzrodt M, Hilgendorf I, et al. Innate response activator B cells protect against microbial sepsis. Science. 2012;335:597–601.PubMedPubMedCentralCrossRef
117.
Monserrat J, de Pablo R, Diaz-Martin D, Rodriguez-Zapata M, de la Hera A, Prieto A, et al. Early alterations of B cells in patients with septic shock. Crit Care. 2013;17:R105.PubMedPubMedCentralCrossRef
118.
Bermejo-Martin JF, Rodriguez-Fernandez A, Herran-Monge R, Andaluz-Ojeda D, Muriel-Bombin A, Merino P, et al. Immunoglobulins IgG1, IgM and IgA: a synergistic team influencing survival in sepsis. J Intern Med. 2014;276:404–12.PubMedCrossRef
119.
120.
121.
Elphick GF, Sarangi PP, Hyun YM, Hollenbaugh JA, Ayala A, Biffl WL, et al. Recombinant human activated protein C inhibits integrin-mediated neutrophil migration. Blood. 2009;113:4078–85.PubMedPubMedCentralCrossRef
122.
Hutchins NA, Unsinger J, Hotchkiss RS, Ayala A. The new normal: immunomodulatory agents against sepsis immune suppression. Trends Mol Med. 2014;20:224–33.PubMedPubMedCentralCrossRef
123.
124.
Ceeraz S, Nowak EC, Noelle RJ. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol. 2013;34:556–63.PubMedCrossRef
125.
Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013;13:260–8.PubMedPubMedCentralCrossRef
126.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.PubMedPubMedCentralCrossRef
127.
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.PubMedPubMedCentralCrossRef
128.
Laudanski K, Miller-Graziano C, Xiao W, Mindrinos MN, Richards DR, De A, et al. Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways. Proc Natl Acad Sci USA. 2006;103:15564–9.PubMedPubMedCentralCrossRef
129.
Huang X, Venet F, Wang YL, Lepape A, Yuan Z, Chen Y, et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci USA. 2009;106:6303–8.PubMedPubMedCentralCrossRef
130.
Zhang Y, Zhou Y, Lou J, Li J, Bo L, Zhu K, et al. PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Crit Care. 2010;14:R220.PubMedPubMedCentralCrossRef
131.
Unsinger J, McGlynn M, Kasten KR, Hoekzema AS, Watanabe E, Muenzer JT, et al. IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol. 2010;184:3768–79.PubMedPubMedCentralCrossRef
132.
Li WQ, Guszczynski T, Hixon JA, Durum SK. Interleukin-7 regulates Bim proapoptotic activity in peripheral T-cell survival. Mol Cell Biol. 2010;30:590–600.PubMedCrossRef
133.
Sportes C, Hakim FT, Memon SA, Zhang H, Chua KS, Brown MR, et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med. 2008;205:1701–14.PubMedPubMedCentralCrossRef
134.
Morre M, Beq S. Interleukin-7 and immune reconstitution in cancer patients: a new paradigm for dramatically increasing overall survival. Target Oncol. 2012;7:55–68.PubMedPubMedCentralCrossRef
135.
Lu J, Giuntoli RL 2nd, Omiya R, Kobayashi H, Kennedy R, Celis E. Interleukin 15 promotes antigen-independent in vitro expansion and long-term survival of antitumor cytotoxic T lymphocytes. Clin Cancer Res. 2002;8:3877–84.PubMed
136.
Inoue S, Unsinger J, Davis CG, Muenzer JT, Ferguson TA, Chang K, et al. IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. J Immunol. 2010;184:1401–9.PubMedCrossRef
137.
Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med. 2009;180:640–8.PubMedCrossRef
138.
Munoz C, Carlet J, Fitting C, Misset B, Bleriot JP, Cavaillon JM. Dysregulation of in vitro cytokine production by monocytes during sepsis. J Clin Invest. 1991;88:1747–54.PubMedPubMedCentralCrossRef
139.
Ferguson NR, Galley HF, Webster NR. T helper cell subset ratios in patients with severe sepsis. Intensive Care Med. 1999;25:106–9.PubMedCrossRef
140.
Flohe SB, Agrawal H, Flohe S, Rani M, Bangen JM, Schade FU. Diversity of interferon gamma and granulocyte-macrophage colony-stimulating factor in restoring immune dysfunction of dendritic cells and macrophages during polymicrobial sepsis. Mol Med. 2008;14:247–56.PubMedPubMedCentralCrossRef
141.
Leentjens J, Kox M, Koch RM, Preijers F, Joosten LA, van der Hoeven JG, et al. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med. 2012;186:838–45.PubMedCrossRef
142.
Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11:597–610.PubMed
143.
144.
Shankar-Hari M, Lord GM. How might a diagnostic microRNA signature be used to speed up the diagnosis of sepsis? Expert Rev Mol Diagn. 2014;14:249–51.PubMedCrossRef
145.
Tacke F, Roderburg C, Benz F, Cardenas DV, Luedde M, Hippe HJ, et al. Levels of circulating miR-133a are elevated in sepsis and predict mortality in critically ill patients. Crit Care Med. 2014;42:1096–104.PubMedCrossRef
146.
Ma Y, Vilanova D, Atalar K, Delfour O, Edgeworth J, Ostermann M, et al. Genome-wide sequencing of cellular microRNAs identifies a combinatorial expression signature diagnostic of sepsis. PLoS ONE. 2013;8:e75918.PubMedPubMedCentralCrossRef
147.
Wang H, Zhang P, Chen W, Feng D, Jia Y, Xie L. Serum microRNA signatures identified by Solexa sequencing predict sepsis patients’ mortality: a prospective observational study. PLoS ONE. 2012;7:e38885.PubMedPubMedCentralCrossRef
148.
Dorhoi A, Iannaccone M, Farinacci M, Fae KC, Schreiber J, Moura-Alves P, et al. MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment. J Clin Invest. 2013;123:4836–48.PubMedPubMedCentralCrossRef
149.
Rossato M, Curtale G, Tamassia N, Castellucci M, Mori L, Gasperini S, et al. IL-10-induced microRNA-187 negatively regulates TNF-alpha, IL-6, and IL-12p40 production in TLR4-stimulated monocytes. Proc Natl Acad Sci USA. 2012;109:E3101–10.PubMedPubMedCentralCrossRef
150.
151.
Yekebas EF, Eisenberger CF, Ohnesorge H, Saalmuller A, Elsner HA, Engelhardt M, et al. Attenuation of sepsis-related immunoparalysis by continuous veno-venous hemofiltration in experimental porcine pancreatitis. Crit Care Med. 2001;29:1423–30.PubMedCrossRef
152.
Kumagai T, Takeyama N, Yabuki T, Harada M, Miki Y, Kanou H, et al. Apheresis of activated leukocytes with an immobilized polymyxin B filter in patients with septic shock. Shock. 2010;34:461–6.PubMedCrossRef
153.
Reilly D, Taylor MA, Beattie NG, Campbell JH, McSharry C, Aitchison TC, et al. Is evidence for homoeopathy reproducible? Lancet. 1994;344:1601–6.PubMedCrossRef
154.
Linde K, Clausius N, Ramirez G, Melchart D, Eitel F, Hedges LV, et al. Are the clinical effects of homeopathy placebo effects? A meta-analysis of placebo-controlled trials. Lancet. 1997;350:834–43.PubMedCrossRef
155.
Frass M, Linkesch M, Banyai S, Resch G, Dielacher C, Lobl T, et al. Adjunctive homeopathic treatment in patients with severe sepsis: a randomized, double-blind, placebo-controlled trial in an intensive care unit. 2005. Homeopathy. 2011;100:95–100.PubMedCrossRef
156.
Da Rocha Piemonte M, De Freitas Buchi D. Analysis of IL-2, IFN-gamma and TNF-alpha production, alpha5 beta1 integrins and actin filaments distribution in peritoneal mouse macrophages treated with homeopathic medicament. J Submicrosc Cytol Pathol. 2002;34:255–63.PubMed
157.
Erhard M, Kellner J, Wild J, Lösch U, Hatiboglu FS. Effect of echinacea, aconitum, lachesis and apis extracts, and their combinations on phagocytosis of human granulocytes. Phytotherapy Research. 1994;8:14–7.CrossRef
Metadata
Title
Role of cellular events in the pathophysiology of sepsis
Authors
Chandra Bhan
Pankaj Dipankar
Papiya Chakraborty
Pranita P. Sarangi
Publication date
01-11-2016
Publisher
Springer International Publishing
Published in
Inflammation Research / Issue 11/2016
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-016-0970-x

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