Janus face of complement-driven neutrophil activation during sepsis

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Review

Janus face of complement-driven neutrophil activation during sepsis R. Halbgebauera, C.Q. Schmidtb, C.M. Karstenc, A. Ignatiusd, M. Huber-Langa,

⁎

a

Institute of Clinical and Experimental Trauma Immunology, Ulm University Hospital, Helmholtzstr. 8/1, 89081 Ulm, Germany Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Helmholtzstr. 20, 89081 Ulm, Germany Institute for Systemic Inflammation Research, University of Luebeck, Ratzeburger Allee 160, 23562 Luebeck, Germany d Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Helmholtzstr. 14, 89081 Ulm, Germany b c

A R T I C L E I N F O

A B S T R A C T

Keywords: Complement Neutrophils Infection Sepsis Organ dysfunction Multiple organ failure

During local and systemic inflammation, the complement system and neutrophil granulocytes are activated not only by pathogens, but also by released endogenous danger signals. It is recognized increasingly that complement-mediated neutrophil activation plays an ambivalent role in sepsis pathophysiology. According to the current definition, the onset of organ dysfunction is a hallmark of sepsis. The preceding organ damage can be caused by excessive complement activation and neutrophil actions against the host, resulting in bystander injury of healthy tissue. However, in contrast, persistent and overwhelming inflammation also leads to a reduction in neutrophil responsiveness as well as complement components and thus may render patients at enhanced risk of spreading infection. This review provides an overview on the molecular and cellular processes that link complement with the two-faced functional alterations of neutrophils in sepsis. Finally, we describe novel tools to modulate this interplay beneficially in order to improve outcome.

1. Introduction The first phase of the innate immune surveillance comprises neutrophil granulocytes as a cellular and the complement system as a fluidphase defense strategy. Both are activated during local and systemic inflammation when exposed to pathogen- or damage-associated molecular patterns (PAMPs and DAMPs, respectively). However, the subsequent temporal-spatial response of the defense systems is frequently Janus-faced. In ancient Roman myths, the double-faced god Janus was responsible for beginnings, gates, transition, time and duality. As indicated in the present review, neutrophil granulocytes reveal many Janus-faced features during sepsis, particularly when interacting with the complement system. Neutrophils account for the majority of leukocytes in whole blood, and during sepsis, their numbers can be either significantly increased or reduced. Previously, sepsis was defined as an infection-induced systemic inflammatory response syndrome including the clinical signs of tachypnea, tachycardia, fever and, of note, leukocytosis or leukopenia. According to the current definition, sepsis reflects a life-threatening

organ dysfunction, which features an altered mental state, respiratory rate ≥22/min or a systolic blood pressure of ≤100 mmHg, hallmarks caused by a dysregulated host response to infection [1]. As addressed by this review, activation of neutrophils and the complement system can significantly contribute to the impaired host response and organ dysfunction on multiple organ levels. Septic shock additionally exhibits circulatory and cellular/metabolic dysfunction and is associated with an overall higher mortality. Patients with septic shock are identified by the requirement of vasopressors to maintain a mean arterial pressure of ≥65 mmHg and serum lactate levels ≥ 2 mmol/L (> 18 mg/dL) in the absence of hypovolemia [1]. As described below in detail, the current definition of septic shock includes, as new criteria, significant changes in the cellular and fluid-phase innate immune responses. 2. Complement activation during sepsis: insights from the current and former definitions of sepsis Former criteria of sepsis defined this condition as a systemic inflammatory response to an infection [2] that is associated with local

Abbreviations: C3aR, C3a receptor; C5aR1/2, C5a receptor 1/2; CLP, cecal ligation and puncture; CXCR4, C-X-C chemokine receptor type 4; DAMPs/PAMPs, damage-/pathogenassociated molecular patterns; Efb, extracellular fibrinogen-binding protein; ERK, extracellular signal-regulated kinases; fH, factor H; IgG, immunoglobulin G; IL, interleukin; LPS, lipopolysaccharide; MAC, membrane-attack complex; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NETs, neutrophil extracellular traps; NF-κB, nuclear factor kappalight-chain-enhancer of activated B cells; NO, nitric oxide; PI-3K, phosphatidylinositide 3-kinase; ROS, reactive oxygen species; S1P, sphingosine-1-phosphate; SDF-1, stromal cell-derived factor 1; SOFA, sequential organ failure assessment; TCC, terminal complement complex; TLR, toll-like receptor; TNF, tumor necrosis factor ⁎ Corresponding author. E-mail addresses: [email protected] (R. Halbgebauer), [email protected] (C.Q. Schmidt), [email protected] (C.M. Karsten), [email protected] (A. Ignatius), [email protected] (M. Huber-Lang). https://doi.org/10.1016/j.smim.2018.02.004 Received 12 December 2017; Received in revised form 6 February 2018; Accepted 7 February 2018 1044-5323/ © 2018 Elsevier Ltd. All rights reserved.

Please cite this article as: Halbgebauer, R., Seminars in Immunology (2018), https://doi.org/10.1016/j.smim.2018.02.004

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Fig. 1. Complement-dependent functions of neutrophils under non-septic conditions. Activation of the complement system results in opsonization and membrane-attack complex (MAC) formation on the microbial surface. Simultaneous stimulation of neutrophils via respective complement receptors leads to cellular activation and induction of the respiratory burst, phagocytosis of complement-opsonized particles and intracellular germ killing as well as the release of antimicrobial substances for extracellular defense. In addition to the secretion of several proteases that facilitate permeation into inflamed or infected tissue, complement stimulus and binding of toll-like receptor (TLR) ligands induce intracellular signaling pathways that further enhance the pro-inflammatory response. Secretion of neutrophil elastase can reinforce C3 activation by cleaving the F(ab’) fragment off immunoglobulins which, together with dimeric C3b and naturally occurring antibodies, can form a C3 convertase precursor. Antifungal defense is also dependent on sensing via complement receptor 3 (CR3) and induction of phagocytosis of opsonized fungi. Abbreviations: C1q, complement component C1q; C3aR, C3a receptor; C5aR1/2, C5a receptor 1/2; CD11b, cluster of differentiation 11b; Efb, extracellular fibrinogen-binding protein; IgG, immunoglobulin G; NADPH, reduced nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; NETs, neutrophil extracellular traps; p47phox, 47 kDa subunit of NADPH oxidase.

from intracellular stores, for example, in association with the formation of neutrophil extracellular traps (NETs), to kill bacteria [13]. Additionally, natural antibodies that recognize microbial surfaces may contribute to sepsis-induced direct complement activation [14,15]. According to the current definition of sepsis, the initiation and particularly the further progression of complement activation has also to be considered for the diagnosis in addition to the key feature of organ dysfunction because of a dysregulated host response to infection [1]. It is important to note that after surgical control and antibiotic treatment there may still be ongoing complement activation, systemically or locally in a compartmentalized manner. Therefore, the differential temporal-spatial activation of complement in various organs may more accurately reflect the new sepsis definitions. Kidneys, for example, locally produce C3, which can be activated and deposited during sepsis [16]. Factor B is upregulated in renal tubule cells upon exposure to tolllike receptor 4 (TLR4) agonists and during experimental sepsis, and is involved in the regulation of sodium-transporter expression [16,17]. Absence of factor B (alternative pathway) was shown to reduce kidney organ injury during the course of sepsis and increase neutrophil migration towards the intraperitoneal infectious source [16]. In the lungs, enhanced myeloperoxidase concentrations are found during sepsis onset, indicating neutrophil infiltration and activation. However, in the absence of factor B or C1q (classical pathway), the local myeloperoxidase level is increased, which is associated with an aggravated structural injury [18]. In the liver, pro-carboxypeptidase B2, which is involved in fibrin degradation, but also cleaves and modulates the activity of C3a and C5a, is upregulated. There is increasing evidence that the anapyhylatoxin C5a is a major driver of sepsis-induced multiple

and systemic complement activation, as is evident by the generation of the factors Bb, C3a, C3b/c, C5a and sC5b–9, the reduction of plasma levels of the zymogens C3 and C4 and the reduction in overall complement hemolytic activity [3,4]. Already 25 years earlier, both complement activation products and neutrophil degranulation markers (e.g. elastase) were found to be specifically increased in nonsurviving sepsis patients and thus correlate with disease severity [5]. Mechanistically, bacterial surfaces and PAMPs can robustly activate complement via the alternative pathway [6], leading to C3b deposition (i.e. opsonization) of microorganisms. The generated anaphylatoxins C3a and C5a form a potent chemotactic gradient, recruiting neutrophils and macrophages to the infection site to foster pathogen phagocytosis (Fig. 1). Of note, proteomic blood analyses from patients with bacteria-positive blood cultures [7] or from trauma patients who developed sepsis after severe injury [8] revealed altered expression levels of complement and coagulation proteins in addition to pathways addressing phagocytic activity and lipid metabolism. Other, pathogen-independent causes for complement activation during sepsis may result from a cross-talk with the serine proteases of the coagulation system [9,10]. In agreement with this, inhibition of both the coagulation and the complement cascade by C1-inhibitor (which inhibits both C1 and factor XII) exhibited protective effects in baboons with sepsis [11]. However, recent data from Escherichia coli-induced sepsis-like conditions in baboons suggested that there is no major contribution from the coagulation system to complement activation during sepsis [12]. Complement may also be activated via pentraxins, which function as soluble pattern recognition molecules that can activate the classical complement pathway. Upon exposure to bacteria and PAMPs, neutrophils can release pentraxin 3 2

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Fig. 2. Massive complement activation and the two-sided response in neutrophils during sepsis. Systemic inflammation induces a Janus-faced response in neutrophils, with a suppression, but also an overreaching reaction to excessive and/or persistent complement activation. Sustained C5a signaling leads to decreased phagocytosis and impaired chemotaxis because of subcortical rearrangements. Tumor necrosis factor (TNF) secretion in response to bacterial stimulus is reduced via inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Numbers of membrane-standing C5aR1 can be diminished by receptor internalization or proteolytic cleavage. A reduction in the 47 kDa subunit of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p47phox) phosphorylation impairs NADPH oxidase function and the capacity of the respiratory burst with consequent diminished bacterial killing. At the other extreme, complement stimulus, presumably enhanced by intracellular C3 cleavage, may induce the release of pattern recognition molecules, which again reinforce local complement activation. Large amounts of released neutrophil extracellular traps (NETs) provide a prothrombotic platform and, together with various proteases, can inflict bystander injury on healthy tissue. A reduced apoptosis rate prolongs the lifespan of activated neutrophils and increases the risk of tissue damage. A higher glycolytic flux to provide sufficient energy necessary for antimicrobial tasks results in increased lactate and proton extrusion, altering conditions in the extracellular micromilieu. C-reactive protein (CRP)dependent shedding of microvesicles into the circulation can enhance the responsiveness of surrounding cells to complement stimulus, but also induce thrombus formation on the microvesicle surface. Lastly, as a link between the two faces of the neutrophil response, phosphorylation of sphingosine-1 by sphingosine-kinase 1 (Sphk1) increases C5aR2 antiinflammatory signaling. Abbreviations: Bcl-xL, B-cell lymphoma-extra large; C5aR1/2, C5a receptor 1/2; CD11b, cluster of differentiation 11b; Efb, extracellular fibrinogen-binding protein; Glut1, glucose transporter 1; NHE1, sodium-proton exchanger 1; pHi, intracellular pH; ROS, reactive oxygen species; S1P, sphingosine-1-phosphate.

alternative pathway, appears to be of specific importance for successful pathogen recognition and removal. Interestingly, while neutrophil chemotactic activity was demonstrated to be dependent on activation of the alternative pathway [6], mice deficient for the alternative-pathway component factor D displayed a loss of control over inflammatory cytokine generation and neutrophil recruitment during cecal ligation and puncture (CLP)-induced sepsis [18]. Complement-activation products, particularly C5a, induce a strong pro-inflammatory and antimicrobial response in neutrophils, which results in a directed migration towards pathogens and secretion of a magnitude of antimicrobial molecules and inflammatory mediators. The C5a signaling on neutrophils is achieved through extracellular signal-regulated kinases (ERK) 1/2, p38 mitogenactivated protein kinase and phosphatidylinositide 3-kinase (PI–3K) [27,28]. In addition, C5a is capable of inducing phosphorylation and translocation of dormant intracellular key enzymes (including p47phox) to the membrane, which then form and activate the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, generating the oxidative burst for effective bacterial killing [23]. However, excessively generated C5a may also desensitize neutrophils to complement stimuli, because neutrophils exposed to high C5a concentrations for a prolonged time display reduced chemotactic and phagocytic activities as well as impaired ROS production [19,23,29]. Complement opsonization of microbes and subsequent recognition

organ dysfunction [19–22], as defined by the new sepsis criteria, likely because of induction of neutrophil dysfunction. Complement activation products appear to define the role of neutrophils at the different barriers within various organs, and act either as gatekeeper or gate breaker, thereby driving subsequent dysfunctions of the endothelium and organ performance. However, although not included in the criteria of the sepsis-related or sequential organ failure assessment (SOFA) score, neutrophil dysfunction may be the actual driver of the overall immune dysfunction that drives organ dysfunction. In this context, it is noteworthy that neutrophil dysfunction as such can appear double-faceted during sepsis: it can be in a hyperactive, auto-aggressive or a completely hypoactive (i.e. paralyzed) state [23] (Fig. 2). 3. Complement-neutrophil interaction for microbial defense during sepsis Complement activation products, including C3a and C5a, but also the surface-bound opsonins C3b and C4b, activate neutrophils via their corresponding cell-membrane receptors. These activated complementactivation products can induce the release of pro-inflammatory cytokines, the generation of reactive oxygen species (ROS) and the formation of NETs and facilitate phagocytosis of opsonized particles [24–26]. In this process, activation of the classical, but particularly of the 3

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cleave the C5aR1 from the neutrophil surface in an autocrine fashion or from unstimulated bystander cells [52,53]. This provides an explanation for the reduced ability of neutrophils for complement-dependent phagocytosis in the presence of high levels of C5a in vitro as well as during disease [38,54–57]. In this regard, it is likely that C5aR internalization and intracellular recycling as well as degradation have an additional effect in reducing the number of membrane-anchored C5aR1 and may thus compromise an appropriate response to a C5a stimulus [58,59]. These mechanisms provide an explanation for the reduced surface levels of C5aR1 on neutrophils isolated from septic patients with a poor prognosis [38,39]. In our previous work, we demonstrated that activated neutrophils are capable of cleaving extracellular C5 to generate functionally intact C5a and may thereby reinforce local or systemic inflammation [60]. Likewise, C3 cleavage by phagocytes and thereby amplification via the alternative pathway can be assumed to occur during sepsis. This effect may be further amplified by secretion of interleukin (IL)-10 which induced the downregulation of surface CD55 on neutrophils during murine sepsis [61]. Interestingly, recent studies have concluded that not only extracellular, but also intracellular complement activation may play a role in regulating neutrophil function during inflammatory processes. It was shown for T cells that basal intracellular C3 activation is important for cell survival, and shuttling of this intracellular system to the cell surface regulates the production of pro-inflammatory cytokines; it is likely that neutrophils use a similar intracellular autocrine regulation system, because they were also found to contain both C3 and C3a [62]. Some groups have suggested that complement activation and alterations in metabolic processes work hand in hand in stimulating activation of the NACHT, LRR and PYD domains-containing protein 3 inflammasome and thereby reinforce production of pro-inflammatory mediators [63,64]. Nevertheless, to date it has not been clarified whether intracellular complement factors are produced by the leukocyte itself or whether they are incorporated from serum as suggested for several peripheral blood cells [65]; their potential role in sepsis still requires investigation.

of opsonin-coated microbes by respective receptors, like the particularly implicated complement receptor 3, may also be necessary for induction of the respiratory burst [30,31]. However, the massive simultaneous activation of the cellular receptors for C5a, C5aR1 and C5aR2 [32,33] as yet appears to be mainly responsible for the overwhelming inflammation and detrimental outcome, as demonstrated in severe murine sepsis [34]. In this regard, several studies have suggested a central role for the interplay between neutrophils and complement in the poor outcome after sepsis [35,36], based on the reduced levels of surface C5aR1 on neutrophils during sepsis [37–39] and because of C5a reducing tumor necrosis factor (TNF) production in response to microbial stimuli by inhibiting nuclear factor ‘kappa-light-chain-enhancer' of activated B cells (NF-κB) signaling [40]. Effective neutrophil activation appears generally indispensable to combat bacterial and fungal infections. However, in a model of pneumococcal colonization and sepsis, neutrophils, in contrast to complement activation, were not necessarily required for protection against spreading pathogens [41]. Another possible cause for ineffective pathogen removal may be an altered phenotype in neutrophil chemotaxis, which can render injured patients at risk for infection. Neutrophils in patients after severe burn injury demonstrated a spontaneous, randomized untargeted migration behavior, which was not present in healthy individuals or burn patients in the absence of sepsis [42]. This effect may be derived from high C5a serum concentrations [43] or, theoretically, from a loss of the chemosensor of neutrophils because of the septic conditions. Furthermore, complement-induced impairment of neutrophil functions during advanced sepsis might also result from the complementorchestrated mobilization of mature and particularly premature neutrophils from the bone marrow. Under healthy conditions, the C3aC3aR axis appears to protect the bone marrow from egress of hematopoietic stem cells [44]. By contrast, C5a(desArg) results in the downregulation of C-X-C chemokine receptor type 4 (CXCR4) on granulocytes as well as in the release of proteases from bone marrow-resident neutrophils, which not only results in matrix protein degradation, but also of stromal cell-derived factor 1 (SDF-1). Therefore, these events lead to an overall inhibition of the homing effects of the SDF-1/CXCR4 path, with C5a(desArg) promoting the egress of granulocytes, which are subsequently followed by hematopoietic stem cells, into peripheral blood [45,46]. Mobilized premature neutrophils may conduct a less targeted, but overall more aggressive inflammatory response [47]. A central mechanism by which complement regulates antimicrobial activity in neutrophils is the inhibition of apoptosis. Under healthy conditions, neutrophils have a relatively short half-life, which increases significantly during sepsis. It has been demonstrated that particularly C5a can induce anti-apoptotic mechanisms that significantly extend neutrophil viability during infection. This is achieved by C5a-mediated up-regulation of B-cell lymphoma-extra large protein expression and down-regulation of pro-apoptotic Bcl-2-like protein 11 expression (through triggering ERK 1/2 and PI–3K signaling [48,49] or regulating the phosphorylation of the Bcl-2-associated death promoter, which also delays neutrophil apoptosis [50]).

5. Immunometabolic alterations in neutrophils Myeloid cells generally are considered to derive their energy primarily from aerobic adenosine triphosphate generation [66]. In accordance with this, neutrophils appear to depend mainly on glycolysis to allow for highly energy-demanding processes, including migration, phagocytosis and ROS formation [67–69]. The few mitochondria found in neutrophils presumably are used mainly to control apoptotic processes [70,71]. We recently demonstrated that neutrophils boost their metabolism after activation by inflammatory mediators, including C5a. This metabolic boost occurs concurrently with an intracellular alkalization and is followed by acidification of the extracellular microenvironment. These effects appear to be achieved through an elevation in glucose transporter 1 to increase the glycolytic flux as well as facilitating the generation of lactate, which can be transported to the extracellular space [72]. Of note, in contrast to a previous study, there was no detectable energy production via the pentose-phosphate pathway, which generates NADPH as an essential cofactor for hydrogen peroxide production [73]; this was true for steady state and in inflammatory conditions [72]. Even so, alterations in intracellular pH were detectable both in vitro after C5a stimulus and in vivo during murine and human sepsis. Several studies have demonstrated that neutrophils are capable of uptake, metabolism, storage, and synthesis of catecholamines under inflammatory and septic conditions [74–77]. Therefore, it can be presumed that neutrophils are sensitive to catecholaminergic stimuli, and they are able to modulate systemic inflammation by either enhancing or dampening catecholamine concentrations during sepsis. In this regard, complement modulation of the functional connection between neutrophils and catecholamines is very likely. Although there is only

4. Neutrophils as complement modulators during sepsis Neutrophils are not only target and effector cells for complement activation stimuli, but are themselves also able to modulate the extent of complement activity. Serum immunoglobulin G (IgG) can be cleaved by neutrophilic elastase, and the resulting F(ab’)2 fragments form immune complexes together with naturally occurring antibodies, which can induce complement activation by binding dimeric C3b as a C3 convertase precursor. This mechanism might also be responsible for some of the excessive complement activation observed in septic patients with enhanced levels of neutrophil-derived elastase [5,51]. Neutrophil proteases secreted upon microbial stimulus can also modulate inflammation in a very contradictory manner; proteases, including cathepsin G and particularly neutrophil elastase, were demonstrated to 4

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neutrophils in lung pathophysiology [92]. Although discrepant reports exist as to whether sepsis without any additional insult may directly lead to acute lung injury [93,94], various studies have shown that blockade of C5a-C5aR1 interaction inhibits sepsis-induced neutrophil recruitment to the bronchoalveolar space and the subsequent pulmonary inflammatory response, and furthermore significantly reduces bacterial load in the lungs and other organs [95]. Blockade of thrombinmediated complement activation by hirudin application reduced both C5a concentrations and neutrophil counts in bronchoalveolar lavage fluids [9]. Moreover, blockade of the C5a-C5aR1 axis also attenuated C5a-primed lung inflammatory response after trauma, including neutrophil recruitment and cytokine release, when challenged with an additional septic insult (LPS as PAMP) [96]. During sepsis, sphingosine kinase 1 is excessively produced by neutrophils (and macrophages), which phosphorylates sphingosine to form the signaling lipid sphingosine-1-phosphate (S1P). In endotoxin-induced acute lung injury, both C5a and LPS generated S1P in neutrophils, which in turn upregulated C5aR2 expression on neutrophils (and macrophages), resulting in antiinflammatory cellular features [97], again a double-faceted response. In the liver, a mutual relationship between acute liver failure and innate immune dysfunction has been proposed [98]. Regarding sepsisinduced bacterial load, a reduction in hepatic bacterial count has been shown when either C5a or factor D was blocked [18,99]. In an Enterococcus faecium-peritonitis model, hepatic clearance of the bacteria was reduced in neutropenic mice, although the acute-phase response, including C3 generation, was enhanced. This indicates the importance of the interactions between complement and neutrophils for effective bacterial killing [100]. In general, hepatocytes upregulate synthesis of coagulation and complement factors during sepsis [101]; inflammatory mediators, including IL‐6, released by Kupffer cells upon LPS exposure can induce C5aR1/2-expression on hepatocytes [102]. In turn, C5a induces the acute-phase response in hepatocytes, with secretion of several pro-inflammatory mediators. Intravenous exposure of rodents to Salmonella enteritidis endotoxin resulted in complement activation, inflammatory mediator release and neutrophilic hepatic injury, which together contribute to hepatic dysfunction [103]. Taken together, complement activation products and neutrophils significantly contribute to hepatic dysfunction in the septic course. Renal dysfunction can be induced directly by sepsis-triggered complement activation: C5a can structurally and functionally alter the glomerular filter (e.g. by loss of podocyte foot processes) and induce classical signs of acute kidney injury (AKI) [19]. Additionally, neutrophils regulated by complement (as highly sensitive immune sensors) can contribute to kidney dysfunction. Systemic infection with Staphylococcus aureus, for example, manipulates the complement system on the C3 level, by releasing the immune-evasion protein extracellular fibrinogen-binding protein (Efb), which targets C3 and in turn can enhance renal bacterial growth, inducing neutrophil-driven renal abscesses [104]. EfB blockade by mini-antibodies results in restoration of C5a levels and neutrophil killing of S. aureus. Renal neutrophil infiltration during AKI development resulting from endotoxemia appears to be dependent on extrarenal TLR4 [105]. To what extent complement-mediated upregulation of endothelial adhesion molecules contributes to the renal neutrophil recruitment during sepsis remains elusive [106]. Complement–neutrophil interactions may also influence sepsis-induced disturbances of hemodynamics. Previously, C5a-primed neutrophils have been demonstrated to phosphorylate adherence junctions in the endothelium of coronary arteries, increasing vascular permeability [107]. Recently, sepsis-induced cardiac dysfunction has been related to the generated anaphylatoxin C5a, which causes signaling defects in cardiomyocytes, electrolyte imbalances and inflammatory responses, including neutrophil infiltration, all of which lead to contractile dysfunction [108–110]. Neutrophil-derived nitric oxide (NO) [111] may also contribute to septic cardiodepression and hemodynamic alterations. C5aR agonists have been demonstrated to induce NO

limited data on modulation of the neutrophil catecholamine regulation, future studies may indicate whether there is a direct involvement of pro-inflammatory complement factors, including C3a and C5a, in this process of regulating central cellular functions during sepsis. 6. Influence of the complement–neutrophil axis on barrier function To achieve rapid and effective bacterial clearance, neutrophils employ an arsenal of functional alterations to facilitate their egress from the bloodstream. Upregulation of integrin activity and selectins, but also stimulation of endothelial cells to increase the expression of the respective ligands, results in enhanced adhesion and thus close proximity to the endothelial wall [78]. Secretion of granules containing matrix metalloproteases and serine proteases then allows neutrophils to loosen endothelial intercellular junctions and facilitates migration into the infected tissue. However, presumably also because of autocrine modulation of cell-surface receptors by proteases secreted upon inflammatory stimuli, including complement activation products [52], directed migration and antimicrobial responses are severely impaired during sepsis [79]. Possibly because of immunosuppression and increased endothelial adherence and migration into infected tissues, total circulating neutrophil numbers can also be substantially decreased in septic shock patients, which correlates with detrimental outcome [80]. However, recent studies have suggested that not total neutrophil numbers, rather the large proportion of immature band neutrophils may be responsible for poor prognosis [81,82]. In this context, it is noteworthy that in several clinically relevant sepsis models, including the murine CLP model, animals regularly respond to polymicrobial challenge with systemic neutropenia rather than with neutrophilia, whereas locally, there is still massive accumulation of mature and immature leukocytes [83]. Immature neutrophils possess large amounts of serine proteases and myeloperoxidase, which, in addition to bacterial killing, can also increase endothelial leakage and inflict bystander injury on healthy tissue [84], and their expression during sepsis correlated with organ dysfunction and death [85]. In this scenario, a direct involvement of complement is very likely, because neutrophil mobilization from the bone marrow is highly dependent on complement activity [86]. In addition to proteases and ROS, neutrophils employ the sophisticated mechanism of NET formation (i.e. NETosis) in combating infection. The release of large amounts of cellular DNA with locally high concentrations of antimicrobial substances allows for effective pathogen binding and killing. However, large amounts of NETs, a highly useful tool in antibacterial defense, can also induce thrombosis and damage the blood-organ barrier [87]. Mostly consistent with these findings, application of granulocyte-colony stimulating factor was not beneficial in non-neutropenic sepsis patients [88,89] and there is considerable debate over its use in neutropenic patients [90]. 7. Complement–neutrophil interaction in sepsis-induced multiple organ dysfunction syndrome Sepsis-induced organ dysfunction is associated with various alterations in innate immunity. Complement interaction with leukocytes may alter the organ response on multiple levels. In the lungs, leukocytes are recruited via complement-induced upregulation of endothelial adhesion molecules, including E-/P-selectin and intercellular adhesion molecule 1, and via the chemoattractive potency of C5a for neutrophils and macrophages [91]. Accumulation of neutrophils within the alveolar space with resultant pulmonary inflammation is a hallmark of acute lung injury and adult respiratory distress syndrome with reduced paO2/FiO2 ratios. More than three decades earlier, bacterial clearance studies demonstrated that intravenous pneumococci failed to localize to the lungs when C5 was absent. Furthermore, C5a-induced pulmonary damage was prevented in neutropenic animals, indicating interaction between complement and 5

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response, bacterial killing and overall survival [19,23]. In translational studies, using a C5 inhibitory strategy (RA101295) in E. coli-induced sepsis in baboons, some protective effects on sepsis-associated coagulopathy, barrier disruption and organ dysfunction have been recently reported [12]. Of note, RA101295 reduced neutrophil activation without affecting phagocytic capacity and inhibited neutrophil sequestration in the lungs [12]. In the same model, compstatin inhibition of the central complement component C3 also revealed protective effects, with amelioration of sepsis-induced leukopenia [129]. In humans with early severe sepsis or septic shock, a recent phase II trial (ClinicalTrials.gov identifier: NCT02246595) applied a neutralizing monoclonal antibody against human C5a (CaCP29) and proposed, reflected in some press releases, a positive trend in the SOFA score, need for ventilator support and length of stay on the intensive care unit. In porcine sepsis, a combined therapeutic approach of both C5 (by coversin) and TLR-cofactor (by CD14 antibodies) blockade improved hemodynamics, inflammatory response, early neutropenia and organ function [130–132]. Furthermore, this double blockade also reduced E. coli-induced tissue factor expression on neutrophils and thereby prevented turning on of the procoagulatory switch of neutrophils [130]. Another sophisticated approach uses a chimeric protein consisting of complement inhibitor human factor H (fH) that binds to S. pyogenes, linked to the Fc region of IgG (FH6-7/Fc), which enables phagocytes (including neutrophils) to kill the bacteria by displacing fH from the bacterial surface during septic conditions [133]. A novel approach has been piloted by the application of bone marrow-derived neutrophils locally (intratracheally) post-trauma to clear bacteria, including Pseudomonas aeruginosa and S. aureus, and thereby inhibit development of pneumonia [134]. It is tempting to speculate that such an approach could also help to clear the pathogens causing sepsis, when applied in a potentially complement-primed and timely manner. For future applications, a novel biomaterial was designed as Fc-functionalized microparticles, spiked with Fc domains of antibodies either pointed outwards or in a non-oriented manner. In the oriented Fc form, complement-activation products, including C5a, can be neutralized on the particle surface, whereas the non-oriented form in addition sequesters significantly less iC3b and membrane-attack complex (MAC) on the artificial microparticle surface, which in turn leads to enhanced soluble MAC concentrations [135]. Theoretically, these microparticles may be used during septic conditions to modify and control complement activation. Naturally, ex vivo-generated neutrophil-derived microparticles, equipped with different coagulation- and/or immune-(metabolic) modulators, could be used in future avenues to prevent sepsis-induced thrombosis, inflammation, metabolic disturbances and cellular dysfunction. However, independent of the specific immune-modulating target, it is important to comprehend exactly the features of the complement and neutrophil defense systems, because both can functionally appear as Janus face − and in consequence, differential therapies are required.

generation by neutrophils and endothelial cells [112]. Taken together, innate immune dysfunction reflected by altered functions of both complement and neutrophils is an integral part and may also represent a major driver of sepsis-associated organ dysfunction and, therefore, needs scientific and clinical attention. 8. Complement diagnostics and therapeutic strategies during sepsis Monitoring complement activation during sepsis remains challenging. It is somewhat surprising that in contrast to classical inflammatory mediators, including C-reactive protein, IL-6 and procalcitonin, plasma concentrations of anaphylatoxin C5a are not enhanced excessively, although a considerable systemic complement activation and depletion occurs, as reflected by a significant reduction in complement hemolytic activity [38,113]. It is assumed that the generated C5a binds to and interacts with the corresponding receptors, which are abundantly expressed on various cell surfaces, particularly on neutrophils, and, therefore, the complement activation products may not prevailingly appear in the circulation [114]. Consequently, an enhanced C3a/C3 ratio may lead to a better assessment of systemic complement activation early during sepsis [5,115]. Remarkably, C3 depletion during abdominal sepsis correlated with the development of coagulation disorders, infectious complications and poor outcome [116]. By contrast, C3b binding on neutrophils was enhanced in septic patients and was associated with increased bactericidal activity [117]. Another approach to detect and even monitor systemic complement activation may be the reduction in C5aR1 and C5aR2 expression on neutrophils. Almost four decades earlier, Solomkin et al. were the first to describe reduced C5a binding on neutrophils during sepsis in humans [43], subsequently verified in a standardized rat sepsis model [19]. Exposure of normal human neutrophils to serum from patients with intra-abdominal sepsis and elevated C5a concentrations resulted in a similar loss of neutrophil C5a-binding capacity [43]. Applying flow cytometry-based methods in septic animals [118] and severely ill patients who developed infectious complications [119] or in patients with septic shock with subsequent poor outcome [37,38], revealed a loss of neutrophil C5aR1. Furthermore, C5aR2 expression similarly was reduced in neutrophils isolated from septic shock patients who developed multiple-organ failure [120]. Although neutrophils may simply represent an easy sampling method for rapid tissue diagnostic purposes, it is important to note that the anaphylatoxin-receptor expression may reveal a different or even reverse expression pattern in other organs. In this regard, in rodents, C5aR binding was decreased on neutrophils but increased in the lung, liver and heart in the course of sepsis [121,122]. Recently, a multi-centered observational study has been completed aiming to evaluate immune-cell flow-based monitoring of C5aR1 on neutrophils, human leukocyte antigens on monocytes and the percentage of regulatory T cells to predict vulnerability to infectious complications [123] (ClinicalTrials.gov identifier: NCT02186522). Overall, C5aR1 detection in neutrophils may function as a reliable method to determine what is targeted by inhibitory strategies of the C5a-C5aR axis, whereas the small differences in C5a plasma concentrations may not be of practical use [38]. In this context, ex vivo monitoring of the C5aR on neutrophils in whole blood upon exposure to well-defined DAMPs and PAMPs associated with functional, C5a-dependent readouts may in future improve bedside applicability and provide a reliable assessment of the complement response. Regarding complement therapeutic strategies during sepsis, multiple approaches on different levels within the cascade have been proposed [124–127]. Protective effects of C5a inhibition on complement activation, organ performance and outcome have been demonstrated numerous times by various groups in different sepsis settings [20,99]. Inhibition of C5a as “too much of a good thing” [128] appears to particularly improve sepsis-induced impairment of neutrophil function and restore chemotactic activity, phagocytic capability, oxidative-burst

Acknowledgements This review was supported by the German Research Foundation (DFG) within the Collaborative Research Center CRC1149 [grant number INST 40/479-1]. The funding source had no involvement in the content of this article. We would like to thank Dr. Stephanie Denk for graphic support. Declarations of interest: none. References [1] M. Singer, C.S. Deutschman, C.W. Seymour, et al., The third international consensus definitions for sepsis and septic shock (Sepsis-3), JAMA 315 (2016) 801–810. [2] R.C. Bone, R.A. Balk, F.B. Cerra, et al., Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society

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