NADPH oxidase controls neutrophilic response to sterile inflammation in mice by regulating the IL-1α/G-CSF axis

Bagaitkar, Juhi; Pech, Nancy; Ivanov, Stoyan; Austin, Anthony M.; Zeng, Melody Y.; Pallat, Sabine; Huang, Guangming; Randolph, Gwendalyn J.; Dinauer, Mary C.

doi:10.1182/blood-2015-05-644773

Cited by 39 publications

(46 citation statements)

References 61 publications

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“…Additional mechanisms by which diminished NADPH oxidase activity might promote inflammation and autoimmunity include impaired digestion of microbes or debris, followed by increased Toll-like receptor stimulation and/or altered redox status of cellular proteins resulting in increased proinflammatory cytokine production via up-regulated MAP kinase, NF-kB, and other pathways (42)(43)(44). Collectively, our results are consistent with the mechanistic notion that reduced NADPH oxidase activity amplifies multiple proinflammatory signaling pathways that synergize with other lupuspredisposing genes in inducing pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Haploinsufficiency of NADPH Oxidase Subunit Neutrophil Cytosolic Factor 2 Is Sufficient to Accelerate Full‐Blown Lupus in NZM 2328 Mice

Jacob

Yoo

et al. 2017

Arthritis & Rheumatology

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Just as patients with chronic granulomatous disease who lack NADPH oxidase rarely develop SLE, NCF-2-null mice on a nonautoimmune background were susceptible to a chronic granulomatous disease-like opportunistic infection but did not develop lupus. In contrast, on a lupus-prone background, even haploinsufficiency of NCF-2 accelerated the development of full-blown lupus disease. This establishes an interaction between reduced oxidase activity and other lupus-predisposing genes, paralleling human SLE-associated variants predicted to have only reduced NADPH oxidase activity.

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Section: Discussionmentioning

confidence: 99%

Haploinsufficiency of NADPH Oxidase Subunit Neutrophil Cytosolic Factor 2 Is Sufficient to Accelerate Full‐Blown Lupus in NZM 2328 Mice

Jacob

Yoo

et al. 2017

Arthritis & Rheumatology

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“…In both cases, the authors have not specifically addressed whether excessive IL-1α and/or IL-1β signaling was responsible for disease caused in these IA models. Interestingly, cells from CGD patients are known to secrete significantly greater amounts of IL-1α and IL-1β in response to inflammatory stimuli [58, 60]. Considering the earlier finding that neutropenic mice infected with C. albicans and subsequently treated with either recombinant IL-1α or IL-1β were partially protected from disease [31], it will be intriguing to assess whether similar cytokine therapies might enhance protective immune responses in neutropenic models of IA.…”

Section: Role Of Il-1α and Il-1β During Invasive Fungal Infectionsmentioning

confidence: 99%

Alarmin(g) the innate immune system to invasive fungal infections

Caffrey

Obar

2016

Current Opinion in Microbiology

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Fungi encounter numerous stresses in a mammalian host, including the immune system, which they must adapt to in order to grow and cause disease. The host immune system tunes its response to the threat level posed by the invading pathogen. We discuss recent findings on how interleukin (IL)-1 signaling is central to tuning the immune response to the virulence potential of invasive fungi, as well as other pathogens. Moreover, we discuss fungal factors that may drive tissue invasion and destruction that regulate IL-1 cytokine release. Moving forward understanding the mechanisms of fungal adaption to the host, together with understanding how the host innate immune system recognizes invading fungal pathogens will increase our therapeutic options for treatment of invasive fungal infections.

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“…Heterozygous breeding of p40 phoxR58A/+ mice was done to generate p40 phoxR58A/R58A and WT (p40 phox+/+ ) littermates to show that p40 phoxR58A/R58A mice had significantly reduced ROS responses and enhanced inflammation compared with both p40 phox+/+ littermates and with purchased C57BL/6J mice. Mice with inactivation of X-CGD mice [24] on a C57BL/6J or B6.SJL-PtrcaPep3b/BoyJ background were obtained from inhouse colonies [25].…”

Section: Methodsmentioning

confidence: 99%

PI(3)P-p40phoxbinding regulates NADPH oxidase activation in mouse macrophages and magnitude of inflammatory responses in vivo

Bagaitkar

Barbu

Perez-Zapata

et al. 2016

Journal of Leukocyte Biology

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Mutations in the leukocyte NADPH oxidase that abrogate superoxide production result in chronic granulomatous disease (CGD), an inherited immunodeficiency associated with recurrent infections and inflammatory complications. The cytosolic regulatory subunit p40 plays a specialized role in stimulating NADPH oxidase activity on intracellular membranes via its phosphatidylinositol 3-phosphate [PI(3)P]-binding domain, as revealed by studies largely focused on neutrophils. Whether PI(3)P-p40-regulated superoxide production contributes to regulating inflammatory responses is not well understood. Here, we report that mice expressing p40 R58A, which lacks PI(3)P binding, had impaired macrophage NADPH oxidase activity and increased sterile inflammation. p40 macrophages exhibited diminished phagosome reactive oxygen species (ROS) in response to certain particulate and soluble ligands, including IgG-opsonized particles and a TLR2 agonist, along with unexpected defects in plasma membrane oxidase activity. Compared with wild-type (WT) mice, p40 mice had elevated numbers of newly recruited neutrophils and monocytes in peritoneal inflammation elicited by zymosan, monosodium urate (MSU) crystals, or sodium periodate. At later time points, higher numbers of inflammatory macrophages in p40 mice were consistent with delayed resolution. Our studies demonstrate a critical role of PI(3)P-p40 binding for optimal activation of the NADPH oxidase in macrophages. Furthermore, selective loss of PI(3)P-regulated NADPH oxidase activity was sufficient to enhance significantly responses to inflammation and delay resolution.

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NADPH oxidase controls neutrophilic response to sterile inflammation in mice by regulating the IL-1α/G-CSF axis

Abstract: Key Points Dysregulated IL-1α in NADPH oxidase null (Cybb KO) mice initiated increased G-CSF–induced neutrophilia, exacerbating sterile inflammation. Reduction of early neutrophilic response promoted resolution in Cybb KO mice.

Cited by 39 publications

References 61 publications

Haploinsufficiency of NADPH Oxidase Subunit Neutrophil Cytosolic Factor 2 Is Sufficient to Accelerate Full‐Blown Lupus in NZM 2328 Mice

Haploinsufficiency of NADPH Oxidase Subunit Neutrophil Cytosolic Factor 2 Is Sufficient to Accelerate Full‐Blown Lupus in NZM 2328 Mice

Alarmin(g) the innate immune system to invasive fungal infections

PI(3)P-p40phoxbinding regulates NADPH oxidase activation in mouse macrophages and magnitude of inflammatory responses in vivo

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