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Critical Care

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Open Access 01-08-2014 | Research

Receptor-interacting protein kinase 3 deficiency inhibits immune cell infiltration and attenuates organ injury in sepsis

Authors: Archna Sharma, Shingo Matsuo, Weng-Lang Yang, Zhimin Wang, Ping Wang

Published in: Critical Care | Issue 4/2014

Abstract

Introduction

Sepsis is defined as a systemic hyper-inflammatory immune response, with a subsequent immune-suppressive phase, which leads to multiple organ dysfunction and late lethality. Receptor-interacting protein kinase 3 (RIPK3)-dependent necrosis is implicated in driving tumor necrosis factor alpha (TNF-α)- and sepsis-induced mortality in mice. However, it is unknown if RIPK3 deficiency has any impact on immune cell trafficking, which contributes to organ damage in sepsis.

Methods

To study this, male wild-type (WT) and RIPK3-deficient (Ripk3 ^-/-) mice on C57BL/6 background were subjected to sham operation or cecal ligation and puncture (CLP)-induced sepsis. Blood and tissue samples were collected 20 hours post-CLP for various measurements.

Results

In our severe sepsis model, the mean survival time of Ripk3 ^-/- mice was significantly extended to 68 hours compared to 41 hours for WT mice. Ripk3 ^-/- mice had significantly decreased plasma levels of TNF-α and IL-6 and organ injury markers compared to WT mice post-CLP. In the lungs, Ripk3 ^-/- mice preserved better integrity of microscopic structure with reduced apoptosis, and decreased levels of IL-6, macrophage inflammatory protein (MIP)-2 and keratinocyte-derived chemokine (KC), compared to WT. In the liver, the levels of MIP-1, MIP-2 and KC were also decreased in septic Ripk3 ^-/- mice. Particularly, the total number of neutrophils in the lungs and liver of Ripk3 ^-/- mice decreased by 59.9% and 66.7%, respectively, compared to WT mice post-CLP. In addition, the number of natural killer (NK) and CD8T cells in the liver decreased by 64.8% and 53.4%, respectively, in Ripk3 ^-/- mice compared to WT mice post-sepsis.

Conclusions

Our data suggest that RIPK3 deficiency modestly protected from CLP-induced severe sepsis and altered the immune cell trafficking in an organ-specific manner attenuating organ injury. Thus, RIPK3 acts as a detrimental factor in contributing to the organ deterioration in sepsis.

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Gaieski DF, Edwards JM, Kallan MJ, Carr BG: Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013, 41: 1167-1174.CrossRefPubMed

Coopersmith CM, Wunsch H, Fink MP, Linde-Zwirble WT, Olsen KM, Sommers MS, Anand KJ, Tchorz KM, Angus DC, Deutschman CS: A comparison of critical care research funding and the financial burden of critical illness in the United States. Crit Care Med. 2012, 40: 1072-1079.CrossRefPubMed

Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, LoVecchio F, Filbin MR, Shapiro NI, Angus DC, The ProCESS Investigators: A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014, 370: 1683-1693.CrossRefPubMed

Gustot T: Multiple organ failure in sepsis: prognosis and role of systemic inflammatory response. Curr Opin Crit Care. 2011, 17: 153-159.CrossRefPubMed

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: 260-268.PubMedCentralCrossRefPubMed

Aziz M, Yang WL, Matsuo S, Sharma A, Zhou M, Wang P: Upregulation of GRAIL is associated with impaired CD4 T cell proliferation in sepsis. J Immunol. 2014, 192: 2305-2314.PubMedCentralCrossRefPubMed

Angus DC, van der Poll T: Severe sepsis and septic shock. N Engl J Med. 2013, 369: 2063-CrossRefPubMed

Aziz M, Jacob A, Yang WL, Matsuda A, Wang P: Current trends in inflammatory and immunomodulatory mediators in sepsis. J Leukoc Biol. 2013, 93: 329-342.PubMedCentralCrossRefPubMed

Hotchkiss RS, Nicholson DW: Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol. 2006, 6: 813-822.CrossRefPubMed

10.

Bantel H, Schulze-Osthoff K: Cell death in sepsis: a matter of how, when, and where. Crit Care. 2009, 13: 173-PubMedCentralCrossRefPubMed

11.

Pinheiro da Silva F, Nizet V: Cell death during sepsis: integration of disintegration in the inflammatory response to overwhelming infection. Apoptosis. 2009, 14: 509-521.CrossRefPubMed

12.

Golstein P, Kroemer G: Cell death by necrosis: towards a molecular definition. Trends Biochem Sci. 2007, 32: 37-43.CrossRefPubMed

13.

Degterev A, Yuan J: Expansion and evolution of cell death programmes. Nat Rev Mol Cell Biol. 2008, 9: 378-390.CrossRefPubMed

14.

Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G: Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol. 2010, 11: 700-714.CrossRefPubMed

15.

Christofferson DE, Yuan J: Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol. 2010, 22: 263-268.PubMedCentralCrossRefPubMed

16.

Sun X, Lee J, Navas T, Baldwin DT, Stewart TA, Dixit VM: RIP3, a novel apoptosis-inducing kinase. J Biol Chem. 1999, 274: 16871-16875.CrossRefPubMed

17.

Yu PW, Huang BC, Shen M, Quast J, Chan E, Xu X, Nolan GP, Payan DG, Luo Y: Identification of RIP3, a RIP-like kinase that activates apoptosis and NFkappaB. Curr Biol. 1999, 9: 539-542.CrossRefPubMed

18.

Pazdernik NJ, Donner DB, Goebl MG, Harrington MA: Mouse receptor interacting protein 3 does not contain a caspase-recruiting or a death domain but induces apoptosis and activates NF-kappaB. Mol Cell Biol. 1999, 19: 6500-6508.PubMedCentralCrossRefPubMed

19.

Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, Dong MQ, Han J: RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science. 2009, 325: 332-336.CrossRefPubMed

20.

He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X: Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009, 137: 1100-1111.CrossRefPubMed

21.

Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, Chan FK: Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009, 137: 1112-1123.PubMedCentralCrossRefPubMed

22.

Moriwaki K, Chan FK: RIP3: a molecular switch for necrosis and inflammation. Genes Dev. 2013, 27: 1640-1649.PubMedCentralCrossRefPubMed

23.

Newton K, Dugger DL, Wickliffe KE, Kapoor N, de Almagro MC, Vucic D, Komuves L, Ferrando RE, French DM, Webster J, Roose-Girma M, Warming S, Dixit VM: Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science. 2014, 343: 1357-1360.CrossRefPubMed

24.

Duprez L, Takahashi N, Van Hauwermeiren F, Vandendriessche B, Goossens V, Vanden Berghe T, Declercq W, Libert C, Cauwels A, Vandenabeele P: RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity. 2011, 35: 908-918.CrossRefPubMed

25.

Linkermann A, Brasen JH, De Zen F, Weinlich R, Schwendener RA, Green DR, Kunzendorf U, Krautwald S: Dichotomy between RIP1- and RIP3-mediated necroptosis in tumor necrosis factor-alpha-induced shock. Mol Med. 2012, 18: 577-586.PubMedCentralCrossRefPubMed

26.

Kaczmarek A, Vandenabeele P, Krysko DV: Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity. 2013, 38: 209-223.CrossRefPubMed

27.

Qiang X, Yang WL, Wu R, Zhou M, Jacob A, Dong W, Kuncewitch M, Ji Y, Yang H, Wang H, Fujita J, Nicastro J, Coppa GF, Tracey KJ, Wang P: Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat Med. 2013, 19: 1489-1495.CrossRefPubMed

28.

Newton K, Sun X, Dixit VM: Kinase RIP3 is dispensable for normal NF-kappa Bs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4. Mol Cell Biol. 2004, 24: 1464-1469.PubMedCentralCrossRefPubMed

29.

Etogo AO, Nunez J, Lin CY, Toliver-Kinsky TE, Sherwood ER: NK but not CD1-restricted NKT cells facilitate systemic inflammation during polymicrobial intra-abdominal sepsis. J Immunol. 2008, 180: 6334-6345.PubMedCentralCrossRefPubMed

30.

Sherwood ER, Lin CY, Tao W, Hartmann CA, Dujon JE, French AJ, Varma TK: Beta 2 microglobulin knockout mice are resistant to lethal intraabdominal sepsis. Am J Respir Crit Care Med. 2003, 167: 1641-1649.CrossRefPubMed

31.

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: 1655-1665.CrossRefPubMed

32.

Wesche-Soldato DE, Chung CS, Gregory SH, Salazar-Mather TP, Ayala CA, Ayala A: CD8+ T cells promote inflammation and apoptosis in the liver after sepsis: role of Fas-FasL. Am J Pathol. 2007, 171: 87-96.PubMedCentralCrossRefPubMed

33.

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: 2295-2301.PubMedCentralCrossRefPubMed

34.

Stromberg PE, Woolsey CA, Clark AT, Clark JA, Turnbull IR, McConnell KW, Chang KC, Chung CS, Ayala A, Buchman TG, Hotchkiss RS, Coopersmith CM: CD4+ lymphocytes control gut epithelial apoptosis and mediate survival in sepsis. FASEB J. 2009, 23: 1817-1825.PubMedCentralCrossRefPubMed

35.

Ayala A, Evans TA, Chaudry IH: Does hepatocellular injury in sepsis involve apoptosis?. J Surg Res. 1998, 76: 165-173.CrossRefPubMed

36.

Hofer S, Brenner T, Bopp C, Steppan J, Lichtenstern C, Weitz J, Bruckner T, Martin E, Hoffmann U, Weigand MA: Cell death serum biomarkers are early predictors for survival in severe septic patients with hepatic dysfunction. Crit Care. 2009, 13: R93-PubMedCentralCrossRefPubMed

37.

Takasu O, Gaut JP, Watanabe E, To K, Fagley RE, Sato B, Jarman S, Efimov IR, Janks DL, Srivastava A, Bhayani SB, Drewry A, Swanson PE, Hotchkiss RS: Mechanisms of cardiac and renal dysfunction in patients dying of sepsis. Am J Respir Crit Care Med. 2013, 187: 509-517.PubMedCentralCrossRefPubMed

38.

Godshall CJ, Scott MJ, Burch PT, Peyton JC, Cheadle WG: Natural killer cells participate in bacterial clearance during septic peritonitis through interactions with macrophages. Shock. 2003, 19: 144-149.CrossRefPubMed

39.

Vermijlen D, Luo D, Froelich CJ, Medema JP, Kummer JA, Willems E, Braet F, Wisse E: Hepatic natural killer cells exclusively kill splenic/blood natural killer-resistant tumor cells by the perforin/granzyme pathway. J Leukocyte Biol. 2002, 72: 668-676.PubMed

40.

Bai X, Wang S, Tomiyama-Miyaji C, Shen J, Taniguchi T, Izumi N, Li C, Bakir HY, Nagura T, Takahashi S, Kawamura T, Iiai T, Okamoto H, Hatakeyama K, Abo T: Transient appearance of hepatic natural killer cells with high cytotoxicity and unique phenotype in very young mice. Scand J Immunol. 2006, 63: 275-281.CrossRefPubMed

Title: Receptor-interacting protein kinase 3 deficiency inhibits immune cell infiltration and attenuates organ injury in sepsis
Authors: Archna Sharma
Shingo Matsuo
Weng-Lang Yang
Zhimin Wang
Ping Wang
Publication date: 01-08-2014
Publisher: BioMed Central
Published in: Critical Care / Issue 4/2014
Electronic ISSN: 1364-8535
DOI: https://doi.org/10.1186/cc13970

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Receptor-interacting protein kinase 3 deficiency inhibits immune cell infiltration and attenuates organ injury in sepsis

Abstract

Introduction

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusions

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