Structural organization of the neutrophil NADPH oxidase: phosphorylation and translocation during priming and activation

Sheppard, Forest R.; Kelher, Marguerite; Moore, Ernest E.; McLaughlin, Nathan; Banerjee, Anirban; Silliman, Christopher C.

doi:10.1189/jlb.0804442

Cited by 329 publications

(310 citation statements)

References 361 publications

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“…Instead, our observations and those of others suggest that LPS and IL-8 protect neutrophils against apoptosis [1,26]. Of interest, both LPS and IL-8 sensitize Nox2 activity by a process called priming, but they cannot induce Nox2 activity directly [46]. This is relevant, as Nox2 activity is essential for NETosis, as evidenced by the inability of CGD neutrophils to undergo NETosis [6].…”

Section: Wwwcell-researchcom | Cell Research Quinten Remijsen Et Almentioning

confidence: 64%

Neutrophil extracellular trap cell death requires both autophagy and superoxide generation

et al. 2010

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Neutrophil extracellular traps (NETs) are extracellular chromatin structures that can trap and degrade microbes. They arise from neutrophils that have activated a cell death program called NET cell death, or NETosis. Activation of NETosis has been shown to involve NADPH oxidase activity, disintegration of the nuclear envelope and most granule membranes, decondensation of nuclear chromatin and formation of NETs. We report that in phorbol myristate acetate (PMA)-stimulated neutrophils, intracellular chromatin decondensation and NET formation follow autophagy and superoxide production, both of which are required to mediate PMA-induced NETosis and occur independently of each other. Neutrophils from patients with chronic granulomatous disease, which lack NADPH oxidase activity, still exhibit PMA-induced autophagy. Conversely, PMA-induced NADPH oxidase activity is not affected by pharmacological inhibition of autophagy. Interestingly, inhibition of either autophagy or NADPH oxidase prevents intracellular chromatin decondensation, which is essential for NETosis and NET formation, and results in cell death characterized by hallmarks of apoptosis. These results indicate that apoptosis might function as a backup program for NETosis when autophagy or NADPH oxidase activity is prevented.

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Section: Wwwcell-researchcom | Cell Research Quinten Remijsen Et Almentioning

confidence: 64%

Neutrophil extracellular trap cell death requires both autophagy and superoxide generation

et al. 2010

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“…A future therapeutic approach would be to specifically target the neutrophil NAPDH oxidase complex, potentially by targeting regulatory small GTPases (47). Selective inhibition of Rac2 would be a suitable target because it is required to activate the NADPH oxidase complex and loss-of-function mutations in this molecule replicate the CGD phenotype (48).…”

Section: Discussionmentioning

confidence: 99%

Reactive Oxygen Species Regulate Neutrophil Recruitment and Survival in Pneumococcal Pneumonia

Marriott

Jackson

Wilkinson³

et al. 2008

Am J Respir Crit Care Med

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Rationale: The role of NADPH oxidase activation in pneumonia is complex because reactive oxygen species contribute to both microbial killing and regulation of the acute pulmonary infiltrate. The relative importance of each role remains poorly defined in communityacquired pneumonia. Objectives: We evaluated the contribution of NADPH oxidasederived reactive oxygen species to the pathogenesis of pneumococcal pneumonia, addressing both the contribution to microbial killing and regulation of the inflammatory response. Methods: Mice deficient in the gp91 phox component of the phagocyte NADPH oxidase were studied after pneumococcal challenge. Measurements and Main Results: gp91 phox2/-mice demonstrated no defect in microbial clearance as compared with wild-type C57BL/6 mice. A significant increase in bacterial clearance from the lungs of gp91 phox2/-mice was associated with increased numbers of neutrophils in the lung, lower rates of neutrophil apoptosis, and enhanced activation. Marked alterations in pulmonary cytokine/ chemokine expression were also noted in the lungs of gp91 phox2/-mice, characterized by elevated levels of tumor necrosis factor-a, KC, macrophage inflammatory protein-2, monocyte chemotactic protein-1, and IL-6. The greater numbers of neutrophils in gp91 phox2/-mice were not associated with increased lung injury. Levels of neutrophil elastase in bronchoalveolar lavage were not decreased in gp91 phox2/-mice. Conclusions: During pneumococcal pneumonia, NADPH oxidasederived reactive oxygen species are redundant for host defense but limit neutrophil recruitment and survival. Decreased NADPH oxidasedependent reactive oxygen species production is well tolerated and improves disease outcome during pneumococcal pneumonia by removing neutrophils from the tight constraints of reactive oxygen species-mediated regulation.

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“…3c). This analysis suggested several such mechanisms, including suppressive soluble factors [12][13][14] , generation of extracellular adenosine [15][16][17][18] , and release of reactive oxygen 19 , and a possible, previously unanticipated role for T R cells in regulating wound repair.…”

mentioning

confidence: 99%

Foxp3-dependent programme of regulatory T-cell differentiation

Gavin

Rasmussen²,

Fontenot³

et al. 2007

Nature

1,018

889

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Regulatory CD4 1 T cells (T R cells), the development of which is critically dependent on X-linked transcription factor Foxp3 (forkhead box P3), prevent self-destructive immune responses 1 . Despite its important role, molecular and functional features conferred by Foxp3 to T R precursor cells remain unknown. It has been suggested that Foxp3 expression is required for both survival of T R precursors as well as their inability to produce interleukin (IL)-2 and independently proliferate after T-cell-receptor engagement, raising the possibility that such 'anergy' and T R suppressive capacity are intimately linked 2-4 . Here we show, by dissociating Foxp3-dependent features from those induced by the signals preceding and promoting its expression in mice, that the latter signals include several functional and transcriptional hallmarks of T R cells. Although its function is required for T R cell suppressor activity, Foxp3 to a large extent amplifies and fixes pre-established molecular features of T R cells, including anergy and dependence on paracrine IL-2. Furthermore, Foxp3 solidifies T R cell lineage stability through modification of cell surface and signalling molecules, resulting in adaptation to the signals required to induce and maintain T R cells. This adaptation includes Foxp3-dependent repression of cyclic nucleotide phosphodiesterase 3B, affecting genes responsible for T R cell homeostasis.In males, Foxp3 deficiency results in fatal early-onset systemic autoimmune disease 5 . In heterozygote Foxp3 wt/null females only one-half of T cells harbours the mutant Foxp3 allele due to random X-chromosome inactivation, whereas autoimmunity is controlled by a normal T R population expressing the Foxp3 wild-type allele. Thus, we were able to genetically mark cells actively transcribing a Foxp3 null allele, yet lacking Foxp3 protein (hereafter called T FN for Foxp3 nullexpressing T cells), through an in-frame insertion of GFP into a stop-codon-disrupted Foxp3 locus (Foxp3 gfpko ) and investigate their features in mice ( Fig. 1a; see also Supplementary Figs 1 and 2a). Female Foxp3 gfpko/wt mice were healthy, whereas male Foxp3 gfpko mice developed the same severity of autoimmunity as Foxp3 knockout (Foxp3 null ) mice 6 , resulting in death at ,4 weeks of age. Thymocyte and peripheral lymphoid organ cellularity did not differ between Foxp3 gfpko/wt and Foxp3 gfp/gfp mice, nor did the proportion of Foxp3 1 T R cells and Foxp3 2 CD4 1 T cells (data not shown). As our main focus was to characterize T FN cells in healthy Foxp3 gfpko/wt mice, analysis of autoimmune male Foxp3 gfpko mice is included as Supplementary Fig. 2.T FN cells constituted ,1-3% of mature CD4 1 thymocytes and peripheral CD4 1 T cells, indicating that Foxp3 is not required to rescue T R precursors from negative selection (Fig. 1b, c). This is consistent with a reported abundance of T-cell receptors (TCRs) characteristic of T R cells in Foxp3 null mice 7 . As ectopic expression of Foxp3 has been shown to induce a state of hyporesponsiveness in CD4 1 T cell...

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Structural organization of the neutrophil NADPH oxidase: phosphorylation and translocation during priming and activation

Cited by 329 publications

References 361 publications

Neutrophil extracellular trap cell death requires both autophagy and superoxide generation

Neutrophil extracellular trap cell death requires both autophagy and superoxide generation

Reactive Oxygen Species Regulate Neutrophil Recruitment and Survival in Pneumococcal Pneumonia

Foxp3-dependent programme of regulatory T-cell differentiation

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