Extracellular Histones Are Essential Effectors of C5aR- and C5L2-mediated Tissue Damage and Inflammation in Acute Lung Injury

Overview

Journal FASEB J

Specialties Biology
Physiology

Date 2013 Aug 29

PMID 23982144

Citations 129

Authors

Markus Bosmann

Jamison J Grailer

Robert Ruemmler

Norman F Russkamp

Firas S Zetoune

J Vidya Sarma

Theodore J Standiford

Peter A Ward

Affiliations

Soon will be listed here.

Abstract

We investigated how complement activation promotes tissue injury and organ dysfunction during acute inflammation. Three models of acute lung injury (ALI) induced by LPS, IgG immune complexes, or C5a were used in C57BL/6 mice, all models requiring availability of both C5a receptors (C5aR and C5L2) for full development of ALI. Ligation of C5aR and C5L2 with C5a triggered the appearance of histones (H3 and H4) in bronchoalveolar lavage fluid (BALF). BALF from humans with ALI contained H4 histone. Histones were absent in control BALF from healthy volunteers. In mice with ALI, in vivo neutralization of H4 with IgG antibody reduced the intensity of ALI. Neutrophil depletion in mice with ALI markedly reduced H4 presence in BALF and was highly protective. The direct lung damaging effects of extracellular histones were demonstrated by airway administration of histones into mice and rats (Sprague-Dawley), which resulted in ALI that was C5a receptor-independent, and associated with intense inflammation, PMN accumulation, damage/destruction of alveolar epithelial cells, together with release into lung of cytokines/chemokines. High-resolution magnetic resonance imaging demonstrated lung damage, edema and consolidation in histone-injured lungs. These studies confirm the destructive C5a-dependent effects in lung linked to appearance of extracellular histones.

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References

Matthay M, Ware L, Zimmerman G . The acute respiratory distress syndrome. J Clin Invest. 2012; 122(8):2731-40. PMC: 3408735. DOI: 10.1172/JCI60331. View

Larsen G, McCarthy K, Webster R, Henson J, Henson P . A differential effect of C5a and C5a des Arg in the induction of pulmonary inflammation. Am J Pathol. 1980; 100(1):179-92. PMC: 1903777. View

Abrams S, Zhang N, Manson J, Liu T, Dart C, Baluwa F . Circulating histones are mediators of trauma-associated lung injury. Am J Respir Crit Care Med. 2012; 187(2):160-9. PMC: 3570656. DOI: 10.1164/rccm.201206-1037OC. View

Bernard G, Artigas A, Brigham K, Carlet J, Falke K, Hudson L . The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994; 149(3 Pt 1):818-24. DOI: 10.1164/ajrccm.149.3.7509706. View

Zhang X, Schmudde I, Laumonnier Y, Pandey M, Clark J, Konig P . A critical role for C5L2 in the pathogenesis of experimental allergic asthma. J Immunol. 2010; 185(11):6741-52. DOI: 10.4049/jimmunol.1000892. View

Hawlisch H, Belkaid Y, Baelder R, Hildeman D, Gerard C, Kohl J . C5a negatively regulates toll-like receptor 4-induced immune responses. Immunity. 2005; 22(4):415-26. DOI: 10.1016/j.immuni.2005.02.006. View

Chen N, Mirtsos C, Suh D, Lu Y, Lin W, McKerlie C . C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a. Nature. 2007; 446(7132):203-7. DOI: 10.1038/nature05559. View

Li R, Coulthard L, Wu M, Taylor S, Woodruff T . C5L2: a controversial receptor of complement anaphylatoxin, C5a. FASEB J. 2012; 27(3):855-64. DOI: 10.1096/fj.12-220509. View

Xu J, Zhang X, Pelayo R, Monestier M, Ammollo C, Semeraro F . Extracellular histones are major mediators of death in sepsis. Nat Med. 2009; 15(11):1318-21. PMC: 2783754. DOI: 10.1038/nm.2053. View

10.

Fuchs T, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers Jr D . Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010; 107(36):15880-5. PMC: 2936604. DOI: 10.1073/pnas.1005743107. View

11.

Lalli P, Strainic M, Yang M, Lin F, Medof M, Heeger P . Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis. Blood. 2008; 112(5):1759-66. PMC: 2518884. DOI: 10.1182/blood-2008-04-151068. View

12.

Wetsel R . Expression of the complement C5a anaphylatoxin receptor (C5aR) on non-myeloid cells. Immunol Lett. 1995; 44(2-3):183-7. DOI: 10.1016/0165-2478(94)00212-a. View

13.

Kwan W, van der Touw W, Paz-Artal E, Li M, Heeger P . Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells. J Exp Med. 2013; 210(2):257-68. PMC: 3570105. DOI: 10.1084/jem.20121525. View

14.

Li P, Li M, Lindberg M, Kennett M, Xiong N, Wang Y . PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med. 2010; 207(9):1853-62. PMC: 2931169. DOI: 10.1084/jem.20100239. View

15.

Gerard C, Gerard N . C5A anaphylatoxin and its seven transmembrane-segment receptor. Annu Rev Immunol. 1994; 12:775-808. DOI: 10.1146/annurev.iy.12.040194.004015. View

16.

Ward P . Acute lung injury: how the lung inflammatory response works. Eur Respir J Suppl. 2003; 44:22s-23s. DOI: 10.1183/09031936.03.00000703a. View

17.

Monestier M, Fasy T, Losman M, Novick K, Muller S . Structure and binding properties of monoclonal antibodies to core histones from autoimmune mice. Mol Immunol. 1993; 30(12):1069-75. DOI: 10.1016/0161-5890(93)90153-3. View

18.

Brinkmann V, Zychlinsky A . Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol. 2007; 5(8):577-82. DOI: 10.1038/nrmicro1710. View

19.

Allam R, Scherbaum C, Darisipudi M, Mulay S, Hagele H, Lichtnekert J . Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4. J Am Soc Nephrol. 2012; 23(8):1375-88. PMC: 3402284. DOI: 10.1681/ASN.2011111077. View

20.

Paine 3rd R, Standiford T, Dechert R, Moss M, Martin G, Rosenberg A . A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury. Crit Care Med. 2011; 40(1):90-7. PMC: 3242850. DOI: 10.1097/CCM.0b013e31822d7bf0. View