Elsevier

Molecular Immunology

Volume 102, October 2018, Pages 32-41
Molecular Immunology

Role of complement C5a and histones in septic cardiomyopathy

https://doi.org/10.1016/j.molimm.2018.06.006Get rights and content

Highlights

  • ā€¢

    Cardiomyopathy is a common complication of sepsis which can lead to high mortality rates (āˆ¼70%).

  • ā€¢

    Cardiac dysfunction of sepsis disappears after recovery from sepsis, indicating cardiac dysfunction is reversible.

  • ā€¢

    Cardiomyopathy is dependent on complement C5a and its receptors, which develop during early sepsis.

  • ā€¢

    During sepsis, cardiac dysfunction is related to C5a and its extracellular histones, leading to cardiomyopathy of sepsis.

  • ā€¢

    Activation of NLRP3 inflammasome and MAPKs in CMs are also involved in the process of septic cardiomyopathy.

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-1Ī² 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).

Introduction

Sepsis in United States kills more than 200,000 individuals per year and epidemiological studies show an increased incidence of deaths from sepsis and septic shock over the past two decades in US (Kumar et al., 2011; Martin et al., 2003). Sepsis and septic shock are the most common cause of death among critically ill patients in intensive care units (ICUs) with estimated annual costs of care exceeding $17 billion (Angus et al., 2001; Dombrovskiy et al., 2007; Russell, 2006). Despite nearly 100 clinical trials, there are no FDA-approved drugs for use in sepsis. We do not adequately understand the molecular events in sepsis in ways that have translational implications. Pathogenesis of sepsis is complex, with many immune and non-immune mediators involved. In 1904, William Osler noted, "It appears that patients are dying not from their infections but rather their reaction to them. Sepsis has traditionally been considered to be a result of an uncontrolled inflammatory response that results in organ dysfunction (Cho and Choi, 2014). Four key areas in sepsis are endothelial dysfunction, coagulation abnormalities, alterations in cell function, and dysregulated cardiovascular responses (Evans, 2018). It is also now realized that sepsis can cause progressive symptoms developing early as well as weeks, months or years after ā€œrecoveryā€ from sepsis (Delano and Ward, 2016). Aggressive early intervention for managing infection (bacterial cultures and antibiotics therapy), better managing resuscitation fluids and vasopressors, as well as improved mechanical ventilation that avoids barotrauma in patients with sepsis-related acute respiratory distress syndrome (ARDS) have been strongly recommended for improving survival of patients with sepsis (Howell and Davis, 2017; Rhodes et al., 2017). When patients develop septic shock, there is often relentless progression to multi-organ failure and a lethal outcome (Gustot, 2011; Shapiro et al., 2009).

Cardiac dysfunction due to sepsis, ā€œseptic cardiomyopathyā€, can happen in up to 80% of patients with septic shock (Beraud et al., 2014). This condition may lead to mortality rates of 70% in these patients (Romero-Bermejo et al., 2011), even though it is generally agreed that, for patients who survive sepsis, the cardiac defects are reversible, typically within 7ā€“10 days after onset of sepsis (Romero-Bermejo et al., 2011). Sepsis-related cardiac dysfunction does not confer long-term harm to the heart (Parker et al., 1984). Cardiac-dysfunction includes reduced systemic vascular resistance, elevated cardiac output, reduced ventricular function and dilatation of ventricles (Parrillo et al., 1990). Regarding pathogenesis of these events, some time ago a myocardial depressant substance was found in blood of septic patients that had in vitro suppressive effects on cardiomyocyte (CM) contractility and relaxation (Parrillo et al., 1985). Subsequently, it was determined that a variety of proinflammatory cytokines (IL-1Ī², IL-6, TNF) had similar effects on CMs (Carlson et al., 2005; Kumar et al., 1996). Our group found that rodent CMs exposed to C5a released cardiosuppressive cytokines including IL-1Ī², IL-6, and TNF (Atefi et al., 2011). The multiplicity of cytokines with these activities has made it unlikely that in vivo neutralization or use of knock-out (K.O.) mice would effectively protect the heart during sepsis. Other factors that can similarly affect CMs include pathogen-associated molecular patterns (PAMPs) released from bacteria and damage-associated molecular patterns (DAMPs) released from injured tissues or apoptotic cells (Rudiger and Singer, 2013). LPS is a prominent example of a PAMP, while histones (discussed in Section 3.4.) are examples of DAMPs released during sepsis.

Section snippets

Methods to assess heart function in sepsis

There are several non-invasive methods to assess heart function following sepsis including functional (Echocardiography; Echo-Doppler), electrical (electrocardiograms; ECGs) measurements and biomarkers present in the plasma. These techniques are still commonly used in septic patients in the hospital to assess cardiac function and monitor the hemodynamic condition (Barnaby et al., 2018; Beraud et al., 2014; Guerin and Vieillard-Baron, 2016; Haileselassie et al., 2016; Ozdemir et al., 2016;

Role of complement C5a in septic cardiomyopathy

It is known that sepsis causes robust complement activation, resulting in robust generation of C5a and it is also known that pathophysiology of polymicrobial sepsis in mice following CLP is C5a-dependent (Hoesel et al., 2007b; Niederbichler et al., 2006). C5a is a powerful proinflammatory mediator generated at the midpoint of the complement system, interacting with its receptors (C5aR1 and C5aR2) after onset of sepsis. It is reported that interaction of C5a with its receptors is linked to many

Sepsis causes NLRP3 inflammasome activation in CMs in a C5a-dependent manner

The inflammasome is a multiprotein complex that mediates the activation of proteins which are involved in the maturation and secretion of proinflammatory cytokines including IL-1Ī² and IL-18 (Franchi et al., 2009; Martinon et al., 2002) and induction of 'pyroptosis' (cell death induced by bacterial products) (Fink and Cookson, 2005). Caspase-1 (ā€œIL-1 converting enzymeā€) promotes secretion of these proinflammatory cytokines (Franchi et al., 2009). NLRP3 (nucleotide-binding oligomerization

Sepsis induces MAPKs activation in CMs in a C5a-dependent manner

Mitogen-activated protein kinase (MAPK) family includes extracellular signal-regulated kinase (ERK), p38 and c-Jun NH2-terminal kinase (JNK). MAPK signaling is involved in a variety of cellular activities including proliferation, differentiation, survival, and death. Deviation from the strict control of MAPK signaling pathways has been implicated in the many human diseases (Kim and Choi, 2010). Myocardial I/R was reported to activate the MAPKs pathways including ERK1/2, JNK1/2, p38; and other

Conclusions

In this review, we have described in polymicrobial sepsis (following CLP) the appearance of extracellular histones in plasma in a C5a and in an NLRP3 inflammasome-dependent manner. Sepsis also caused MAPKs activation in CMs in a C5a-dependent manner. Collectively these events led to functional abnormalities associated with the ā€œcardiomyopathy of sepsisā€.

Fig. 5 summarizes our current data, linking C5a and C5a receptors and the role of extracellular histones to events that compromise the heart

Acknowledgements

We acknowledge support from the Microscopy and Image Analysis Laboratory (MIL), University of Michigan (UM) Medical School, a multiuser imaging facility supported by a grant from the U.S. National Institutes of Health (NIH) National Cancer Institute; the Oā€™Brien Renal Center, the UM Medical School, the Endowment for the Basic Sciences (EBS), and the UM Department of Cell and Developmental Biology. This study was supported by NIH, General Medicine Grants GM29507 and GM61656 (to PAW). MJD would

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