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Mol Immunol. 2018 Oct;102:32-41. doi: 10.1016/j.molimm.2018.06.006. Epub 2018 Jun 18.

Role of complement C5a and histones in septic cardiomyopathy.

Author information

1
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, United States.
2
Department of Surgery, Division of Acute Care Surgery, University of Michigan, Ann Arbor, MI, United States.
3
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm, Ulm, Germany.
4
Division of Cardiovascular Research, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States.
5
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, United States. Electronic address: pward@umich.edu.

Abstract

Polymicrobial sepsis (after cecal ligation and puncture, CLP) causes robust complement activation with release of C5a. Many adverse events develop thereafter and will be discussed in this review article. Activation of complement system results in generation of C5a which interacts with its receptors (C5aR1, C5aR2). This leads to a series of harmful events, some of which are connected to the cardiomyopathy of sepsis, resulting in defective action potentials in cardiomyocytes (CMs), activation of the NLRP3 inflammasome in CMs and the appearance of extracellular histones, likely arising from activated neutrophils which form neutrophil extracellular traps (NETs). These events are associated with activation of mitogen-activated protein kinases (MAPKs) in CMs. The ensuing release of histones results in defective action potentials in CMs and reduced levels of [Ca2+]i-regulatory enzymes including sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2) and Na+/Ca2+ exchanger (NCX) as well as Na+/K+-ATPase in CMs. There is also evidence that CLP causes release of IL-1β via activation of the NLRP3 inflammasome in CMs of septic hearts or in CMs incubated in vitro with C5a. Many of these events occur after in vivo or in vitro contact of CMs with histones. Together, these data emphasize the role of complement (C5a) and C5a receptors (C5aR1, C5aR2), as well as extracellular histones in events that lead to cardiac dysfunction of sepsis (septic cardiomyopathy).

KEYWORDS:

Cecal ligation and puncture (CLP); Intracellular calcium ([Ca(2+)]i); NLRP3 inflammasome; Na+/Ca(2+)exchanger (NCX); Na+/K+-ATPase; Sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA2)

PMID:
29914696
PMCID:
PMC6139045
[Available on 2019-10-01]
DOI:
10.1016/j.molimm.2018.06.006

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