The Phosphatidylinositol 3-Kinase Signaling Pathway Exerts Protective Effects during Sepsis by Controlling C5a-Mediated Activation of Innate Immune Functions

Wrann, Christiane D.; Tabriz, Navid; Barkhausen, Tanja; Klos, Andreas; Griensven, Martijn van; Pape, Hans-Christian; Kendoff, Daniel; Guo, Renfeng; Ward, Peter A.; Krettek, Christian; Riedemann, Niels C.

doi:10.4049/jimmunol.178.9.5940

Cited by 56 publications

(43 citation statements)

References 39 publications

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“…46 Certainly our findings do not suggest a therapeutic place for PI3K␦ or RhoA inhibitors for prevention of infection in critically ill patients. In contrast, the ability of GM-CSF to restore phagocytosis in nonneutropenic critically ill patients has been described previously, 47 and we also show here that it effectively restores defective transmigration.…”

Section: Discussionmentioning

confidence: 63%

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients

Morris

Brittan

Wilkinson

et al. 2011

Blood

150

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Critically ill patients are at heightened risk for nosocomial infections. The anaphylatoxin C5a impairs phagocytosis by neutrophils. However, the mechanisms by which this occurs and the relevance for acquisition of nosocomial infection remain undetermined. We aimed to characterize mechanisms by which C5a inhibits phagocytosis in vitro and in critically ill patients, and to define the relationship between C5a-mediated dysfunction and acquisition of nosocomial infection. In healthy human neutrophils, C5a significantly inhibited RhoA activation, preventing actin polymerization and phagocytosis. RhoA inhibition was mediated by PI3K␦. The effects on RhoA, actin, and phagocytosis were fully reversed by GM-CSF. Parallel observations were made in neutrophils from critically ill patients, that is, impaired phagocytosis was associated with inhibition of RhoA and actin polymerization, and reversed by GM-CSF. Among a cohort of 60 critically ill patients, C5a-mediated neutrophil dysfunction (as determined by reduced CD88 expression) was a strong predictor for subsequent acquisition of nosocomial infection (relative risk, 5.8; 95% confidence interval, 1.5-22; P ‫؍‬ .0007), and remained independent of time effects as assessed by survival analysis (hazard ratio, 5.0; 95% confidence interval, 1.3-8.3; P ‫؍‬ .01). In conclusion, this study provides new insight into the mechanisms underlying immunocompromise in critical illness and suggests novel avenues for therapy and prevention of nosocomial infection. (Blood. 2011;117(19):5178-5188) IntroductionThe systemic inflammatory response syndrome (SIRS) is classically characterized by profound immune activation, accompanying massive cytokinemia and organ damage. 1,2 However, SIRS is accompanied by a counter-regulatory immune suppression sometimes termed the compensatory anti-inflammatory response syndrome (CARS). 3 This relative immune suppression is considered important for effective resolution of inflammation but may extend to maladaptive counter-regulatory anti-inflammatory responses. 4,5 The consequences of impaired immune function include enhanced susceptibility to nosocomial infection 6 or death from sepsis. 7 Neutrophils are the major front-line cellular defense against bacterial pathogens, and acquired defects in neutrophil function have been identified in both animal and human sepsis 8,9 as well as sterile SIRS. 10,11 However, the mediators driving these defects, and the mechanisms involved, remain uncertain.Animal studies have implicated uncontrolled activation of the complement system in the pathogenesis of sepsis and sterile SIRS. [12][13][14] The key components mediating vasodilatation and vascular leak-the hallmarks of septic shock-are the anaphylatoxins. These are activated forms of complement factors 3 (C3a) and 5 (C5a). 14,15 Animal models of sepsis have also implicated C5a in neutrophil dysfunction. 8 Because of the rapid clearance (2-to 3-minute half life) of C5a from the circulation, measurement of plasma concentrations gives an imprecise account of neutrophil expos...

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Section: Discussionmentioning

confidence: 63%

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients

Morris

Brittan

Wilkinson

et al. 2011

Blood

150

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“…32 Mice deficient in C5L2 have enhanced proinflammatory cytokine responses when stimulated with LPS, and C5L2 has been shown to mediate the ability of C5a to suppress cytokine synthesis in mouse macrophages using a pathway involving phosphoinositol-3 kinase (PI3K). 35,36 In our studies, we are unable to definitively eliminate receptor colocalization or participation of C5L2 in the second-hit response after injury. Furthermore, it is possible that C5a is a messenger of the second-hit response rather than the actual priming stimulus.…”

Section: Discussionmentioning

confidence: 66%

Complement mediates a primed inflammatory response after traumatic lung injury

Hoth¹,

Wells²,

Jones³

et al. 2014

Journal of Trauma and Acute Care Surgery

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BACKGROUND Pulmonary contusion (PC) is a common, potentially lethal injury that results in the priming for exaggerated responses to subsequent immune challenge such as an infection (second hit). We hypothesize a PC-induced complement (C) activation participates in the priming effect for a second hit. METHODS Male, 8 weeks to 9 weeks, C57BL/6 mice (wild-type, C5−/−) underwent blunt chest trauma resulting in PC. At 3 hours/24 hours after injury, the inflammatory response was measured in tissue, serum, and bronchoalveolar lavage (BAL). The thrombin inhibitor, hirudin, was used to determine if injury-induced thrombin participated in the activation of C. Injury-primed responses were tested by challenging injured mice with bacterial endotoxin (lipopolysaccharide, LPS) as a second hit. Inflammatory responses were assessed at 4 hours after LPS challenge. Data were analyzed using one-way analysis of variance with Bonferroni multiple comparison posttest (significance, p ≤ 0.05). Protocols were approved by the Institutional Animal Care and Use Committee. RESULTS We found significantly increased levels of C5a in the BAL of injured animals as early as 24 hours, persisting for up to 72 hours after injury. Hirudin-treated injured mice had significantly decreased levels of thrombin in the BAL that correlated with reduced C5a levels. Injured mice challenged with intratracheal (IT) LPS had increased C5a and inflammatory response. Conversely, inhibition of C5a or its receptor, C5aR, before LPS challenge correlated with decreased inflammatory responses; C5a-deficient mice showed a similar loss of primed response to LPS challenge. CONCLUSION Complement C5a levels in the BAL are increased over several days after PC. Premorbid inhibition of thrombin markedly decreases C5a levels after PC, suggesting that thrombin-induced C activation is the major pathway of activation after PC. Similarly, inhibition of C5a after PC will decrease injury-primed responses to LPS stimulation. Our findings suggest cross-talk between the coagulation and complement systems that induce immune priming after PC.

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“…Using two in vivo inflammation models, we showed that the abrogation of AKT1 markedly promotes the acute inflammatory injuries and potentiates the neutrophil bactericidal capacities, indicating a critical role for AKT1 in regulating neutrophil-mediated acute inflammation. Emerging evidence suggests a role for PI3K/AKT signaling in the regulation of acute and chronic inflammatory processes (14,(40)(41)(42)(43)(44). These findings led to the prospect of considering PI3K or AKT isoforms as promising drug targets for the modulation of inflammatory and autoimmune disorders, cancer, and transplantation (14).…”

Section: Discussionmentioning

confidence: 99%

Kinase AKT1 Negatively Controls Neutrophil Recruitment and Function in Mice

Liu

Wang

et al. 2013

The Journal of Immunology

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Neutrophils are critically involved in host defense and inflammatory injury. However, intrinsic signaling mechanisms controlling neutrophil recruitment and activities are poorly defined. In this article, we showed that protein kinase AKT1 (also known as PKBα) is the dominant isoform expressed in neutrophils and is downregulated upon bacterial infection and neutrophil activation. AKT1 deficiency resulted in severe disease progression accompanied by recruitment of neutrophils and enhanced bactericidal activity in the acute inflammatory lung injury (ALI) and the Staphylococcus aureus infection mouse models. Moreover, the depletion of neutrophils efficiently reversed the aggravated inflammatory response, but adoptive transfer of AKT1−/− neutrophils could potentiate the inflammatory immunity, indicating an intrinsic effect of the neutrophil in modulating inflammation in AKT1−/− mice. In the ALI model, the infiltration of neutrophils into the inflammatory site was associated with enhanced migration capacity, whereas inflammatory stimuli could promote neutrophil apoptosis. In accordance with these findings, neutralization of CXCR2 attenuated neutrophil infiltration and delayed the occurrence of inflammation. Finally, the enhanced bactericidal activity and inflammatory immunity of AKT-deficient neutrophils were mediated by a STAT1-dependent, but not a mammalian target of rapamycin–dependent, pathway. Thus, our findings indicated that the AKT1–STAT1 signaling axis negatively regulates neutrophil recruitment and activation in ALI and S. aureus infection in mice.

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The Phosphatidylinositol 3-Kinase Signaling Pathway Exerts Protective Effects during Sepsis by Controlling C5a-Mediated Activation of Innate Immune Functions

Cited by 56 publications

References 39 publications

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients

Complement mediates a primed inflammatory response after traumatic lung injury

Kinase AKT1 Negatively Controls Neutrophil Recruitment and Function in Mice

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