Reactive Oxygen Species Produced by the NADPH Oxidase 2 Complex in Monocytes Protect Mice from Bacterial Infections

Pizzolla, Angela; Hultqvist, Malin; Nilson, Bo; Grimm, Melissa; Eneljung, Tove; Jonsson, Ing-Marie; Verdrengh, Margareta; Kelkka, Tiina; Gjertsson, Inger; Segal, Brahm H.; Holmdahl, Rikard

doi:10.4049/jimmunol.1103430

Cited by 95 publications

(90 citation statements)

References 51 publications

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“…Thus, calpain KO macrophages and neutrophils failed to mount comparable ROS production to WT control cells, which may explain the delayed bacterial killing we observed. Indeed, ROS production by NADPH oxidase 2 (NOX2) is required to protect mice from spontaneous and recurrent bacterial infections [61]. Our results are also in agreement with a recent study that showed calpain inhibitors dampen ROS production in neutrophils treated with .…”

Section: Discussionsupporting

confidence: 82%

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

et al. 2013

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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...

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Section: Discussionsupporting

confidence: 82%

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

et al. 2013

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“…A mutation in the Ncf1 gene (m1j) (the Ncf1 protein also denoted p47phox) in the B10Q mice, designated as B10Q.Ncf1 m1j/m1j , impairs the expression of the Ncf1 gene, thereby totally blocking the function of the NOX2 complexes, as described earlier (15,18). The B10Q.Ncf1 m1j//m1j .MN + strain has a transgene expressing functional Ncf1 on macrophages using the human CD68 promotor (22,57). This transgene is used when expressed heterozygously, and MN − mice are B10Q.Ncf m1j//m1j littermate controls.…”

Section: Methodsmentioning

confidence: 99%

Mannan induces ROS-regulated, IL-17A–dependent psoriasis arthritis-like disease in mice

Khmaladze

Kelkka

Guérard

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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130

168

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Significance We identified a previously undescribed disease mechanism for psoriasis (Ps) and psoriasis arthritis (PsA)-like disease by developing a new mouse model having characteristic features similar to those of Ps and PsA in human patients. Mannan-induced activation of tissue macrophages triggers IL-17A secretion from γδ T cells, causing Ps-like inflammation. Such inflammation was significantly increased under a reduced oxidative environment. Increased frequency of monocytes/macrophages, depletion experiments, and the disease suppressor function of macrophage-derived reactive oxygen species clearly argue in favor of a role for monocytes/macrophages in this disease model, which is in accordance with the findings in patients with the psoriatic form of skin lesions and arthritis. This novel PsA model could be immensely useful to test new therapeutics for patients with Ps and PsA.

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“…AT1Rs are involved in the cerebrovascular dysfunction induced by ANGII (10). Macrophages are well known to express AT1R and produce ROS in response to ANGII (23,24). Therefore, we sought to determine whether AT1Rs on PVMs participate in the cerebrovascular effects of ANGII.…”

Section: Perivascular Macrophages Mediate the Neurovascular And Cognimentioning

confidence: 99%

“…As the vessels penetrate deeper into the substance of the brain, the glial and vascular basement membranes fuse together and the perivascular space disappears (22). As macrophages, PVMs express AT1Rs and have the potential to produce large amounts of ROS through NOX2 (23,24). To provide more direct evidence that blood-borne ANGII reaches the perivascular space in proximity to PVMs, we administered biotinylated ANGII i.v.…”

Section: Perivascular Macrophages Mediate the Neurovascular And Cognimentioning

confidence: 99%

Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension

Faraco¹,

Sugiyama²,

Lane³

et al. 2016

Journal of Clinical Investigation

278

358

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In this study we investigated the contribution of PVMs to the neurovascular and cognitive dysfunction induced by hypertension. We found that depletion of PVMs in models of chronic hypertension suppresses vascular oxidative stress and ameliorates the attendant impairment in neurovascular coupling and endothelium-dependent responses. Studies in bone marrow (BM) chimeras provided evidence that the dysfunction is mediated by ANGII acting on PVM AT1Rs resulting in NOX2-dependent ROS production. Importantly, concomitant to the neurovascular improvement, PVM depletion also rescued cognitive dysfunction. The findings unveil a previously unrecognized role of PVMs in the neurovascular and cognitive dysfunction induced by hypertension, and identify PVMs as a novel pathogenic component of the NVU of critical importance for brain health.

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Reactive Oxygen Species Produced by the NADPH Oxidase 2 Complex in Monocytes Protect Mice from Bacterial Infections

Cited by 95 publications

References 51 publications

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

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

Mannan induces ROS-regulated, IL-17A–dependent psoriasis arthritis-like disease in mice

Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension

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