Calpastatin Controls Polymicrobial Sepsis by Limiting Procoagulant Microparticle Release

Zafrani, Lara; Gerotziafas, Grigoris; Byrnes, Colleen; Hu, Xiaobang; Perez, Joëlle; Lévi, Charlène; Placier, Sandrine; Letavernier, Emmanuel; Leelahavanichkul, Asada; Haymann, Jean‐Philippe; Elalamy, Ismaı̈l; Miller, Jeffrey L.; Star, Robert A.; Yuen, Peter S.T.; Baud, Laurent

doi:10.1164/rccm.201109-1686oc

Cited by 59 publications

(57 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the CLP model of sepsis, calpain activation peaked within the first 6 h of the immune response [31]. This study also showed that transgenic mice with ubiquitous overexpression of Calpastatin, showed reduced calpain activation and tissue damage following CLP [31]. Interestingly, similar defects in TNF-α and IL-1α production were noted in Calpastatin transgenic mice subjected to CLP [31], as we have observed here in FIP-treated calpain KO mice.…”

Section: Discussionsupporting

confidence: 82%

“…In endotoxemia models, calpain activation also leads to damage of cardiac, lung, and muscle tissues in mice [29,30,52]. In the CLP model of sepsis, calpain activation peaked within the first 6 h of the immune response [31]. This study also showed that transgenic mice with ubiquitous overexpression of Calpastatin, showed reduced calpain activation and tissue damage following CLP [31].…”

Section: Discussionmentioning

confidence: 55%

“…Interestingly, similar defects in TNF-α and IL-1α production were noted in Calpastatin transgenic mice subjected to CLP [31], as we have observed here in FIP-treated calpain KO mice. While differences in bacterial killing were not observed in the Calpastatin transgenic mice following CLP [31], it is important to note that this may reflect differences in the levels of calpain activity required in chronic (CLP) versus acute (FIP) infection models. Our findings suggest that inhibiting calpains may not improve outcomes for cases of peritonitis, due to enhanced risk of bacteremia and developing sepsis.…”

Section: Discussionmentioning

confidence: 92%

“…Unlike its family member IL-1β that is cleaved by inflammasome- [29,30]. Recently, transgenic mice overexpressing Calpastatin were shown to be protected from tissue damage and disseminated intravascular coagulation in the cecal ligation and puncture (CLP) model of sepsis [31]. In this study, Calpastatin was shown to reduce the proinflammatory response, and the levels of procoagulant circulating microparticles.…”

mentioning

confidence: 84%

See 3 more Smart Citations

Calpains promote neutrophil recruitment and bacterial clearance in an acute bacterial peritonitis model

et al. 2013

View full text Add to dashboard Cite

Activation of the innate immune system is critical for clearance of bacterial pathogens to limit systemic infections and host tissue damage. Here, we report a key role for calpain proteases in bacterial clearance in mice with acute peritonitis. Using transgenic mice expressing Cre recombinase primarily in innate immune cells (fes-Cre), we generated conditional capns1 knockout mice. Consistent with capns1 being essential for stability and function of the ubiquitous calpains (calpain-1, calpain-2), peritoneal cells from these mice had reduced levels of calpain-2/capns1, and reduced proteolysis of their substrate selenoprotein K. Using an acute bacterial peritonitis model, we observed impaired bacterial killing within the peritoneum and development of bacteremia in calpain knockout mice. These defects correlated with significant reductions in IL-1α release, neutrophil recruitment, and generation of reactive oxygen species in calpain knockout mice with acute bacterial peritonitis. Peritoneal macrophages from calpain knockout mice infected with enterobacteria ex vivo, were competent in phagocytosis of bacteria, but showed impaired clearance of intracellular bacteria compared with control macrophages. Together, these results implicate calpains as key mediators of effective innate immune responses to acute bacterial infections, to prevent systemic dissemination of bacteria that can lead to sepsis. Keywords: Bacterial infection r Calpains r Neutrophils r Phagocytosis r Reactive oxygen speciesAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionBacterial infection triggers pattern-recognition receptor (PRR) signaling within host cells designed to allow rapid bacterial clearance and avoid progression to systemic infection [1]. In bacterial Correspondence: Dr. Andrew W. B. Craig e-mail: andrew.craig@queensu.ca peritonitis, resident innate immune cells in the peritoneum (e.g. mast cells, macrophages) orchestrate the immune response via rapid release of preformed and de novo generated vasoactive mediators, cytokines, and chemokines [2][3][4]. This leads to recruitment of neutrophils and bacterial capture in neutrophil extracellular traps [5]. Bacterial clearance is facilitated by rapid degranulation, production of ROS and reactive nitrogen species, and phagocytosis by neutrophils and macrophages [6]. Balancing this potent immune response is critical to eliminate the pathogens prior to systemic dissemination and avoid tissue damage observed C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 832Vijay Kumar et al. Eur. J. Immunol. 2014. 44: 831-841 in severe sepsis [3]. Failure to tightly control production of proinflammatory cytokines such as IL-1, are also linked to the development of autoinflammatory disorders [7]. Thus, a better understanding of positive and negative regulation of PRR signaling may inform the development of more effective treatments for these diseases. Calpains are intracellular, calcium (Ca ++ )-dependent cysteine...

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 84%

See 2 more Smart Citations

Calpains promote neutrophil recruitment and bacterial clearance in an acute bacterial peritonitis model

et al. 2013

View full text Add to dashboard Cite

show abstract

“…However, previous studies describe both protective and deleterious effects [4,5]. Converging animal and clinical data have emphasized the role of procoagulant MPs in the initiation of disseminated intravascular coagulation (DIC) during sepsis [6][7][8]. Patients with meningococcal sepsis display elevated numbers of MPs originating from platelets and granulocytes that are prothrombotic [6].…”

mentioning

confidence: 99%