IFN-γ targets macrophage-mediated immune responses toward <i>Staphylococcus aureus</i>

Greenlee‐Wacker, Mallary C.; Nauseef, William M.

doi:10.1189/jlb.4a1215-565rr

Cited by 29 publications

(28 citation statements)

References 47 publications

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“…The ROS produced by neutrophils may contribute to the clearance of apoptotic cells or cell debris, and their deficiency may contribute to inflammation in various ways, including aberrant efferocytosis, for example (58)(59)(60)(61)(62). Alternatively, the inflammation observed in classic CGD and p40 phox deficiency may be due to abnormal ROS production by circulating B cells.…”

Section: Discussionmentioning

confidence: 99%

Inherited p40phox deficiency differs from classic chronic granulomatous disease

Geer¹,

Nieto-Patlán²,

Kuhns³

et al. 2018

Journal of Clinical Investigation

107

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Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40 phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40 phox -deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMAinduced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40 phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD. phox -deficient patient is compound heterozygous for a premature stop codon and a missense mutation in the PX domain that compromises binding to PI(3)P, which results in the impairment of neutrophil phagocytosis-induced oxidase activity (26). As in classic CGD neutrophils, intracellular oxidant production after stimulation with serum-opsonized zymosan (SOZ), IgG beads, or serumopsonized Staphylococcus aureus is impaired in the patient's neutrophils, and S. aureus killing is also defective (20,26,30). However, in this patient, unlike in classic CGD patients, the production of O 2 -by neutrophils in response to stimulation with PMA or formyl-methionyl-leucyl-phenylalanine (fMLF) is normal (26). The killing of S. aureus by neutrophils is also impaired in p40 phox deficiency and classic CGD are largely unknown. Here, we describe the characteristics of 24 patients from 12 families in 8 countries with biallelic mutations of NCF4. The Journal of Clinical Investigation R E S E A R C H A R T I C L E

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Section: Discussionmentioning

confidence: 99%

Inherited p40phox deficiency differs from classic chronic granulomatous disease

Geer¹,

Nieto-Patlán²,

Kuhns³

et al. 2018

Journal of Clinical Investigation

107

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“…To understand the pathogenesis of the tissue necrosis that frequently accompanies severe staphylococcal infections, we probed the molecular mechanisms by which PMN harboring viable CA-MRSA undergo lytic cell death, a terminal event that releases intracellular contents that can act as danger-associated molecular patterns and fuel exuberant inflammation. [8][9][10] To elucidate necroptosis pathways, many investigators have stimulated HT-29 cells with a cocktail of TNFa in the presence of executioner caspase inhibitors (eg, zVAD-fmk) and inhibitors of apoptosis proteins (eg, CHX). Under these experimental conditions, TNFa induces lysis in a RIPK-1-, RIPK-3-, and MLKL-dependent fashion.…”

Section: Discussionmentioning

confidence: 99%

“…[4][5][6] Furthermore, PMN harboring viable S aureus (PMN-SA), particularly CA-MRSA, lyse, 7 thereby serving as a potential source of dangerassociated molecular patterns that could fuel additional inflammation and tissue damage. [8][9][10] The recognition that PMN lysis could contribute to the exuberant inflammation that frequently accompanies infection with CA-MRSA [11][12][13] provides the rationale to investigate the hostmediated mechanism of PMN cell death after phagocytosis of CA-MRSA.…”

Section: Introductionmentioning

confidence: 99%

Lysis of human neutrophils by community-associated methicillin-resistant Staphylococcus aureus

Greenlee‐Wacker

Kremserová

Nauseef

2017

Blood

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Community-associated methicillin-resistant (CA-MRSA) causes infections associated with extensive tissue damage and necrosis. In vitro, human neutrophils fed CA-MRSA lyse by an unknown mechanism that is inhibited by necrostatin-1, an allosteric inhibitor of receptor-interacting serine/threonine kinase 1 (RIPK-1). RIPK-1 figures prominently in necroptosis, a specific form of programmed cell death dependent on RIPK-1, RIPK-3, and the mixed-lineage kinase-like protein (MLKL). We previously reported that necrostatin-1 inhibits lysis of human neutrophils fed CA-MRSA and attributed the process to necroptosis. We now extend our studies to examine additional components in the programmed cell death pathway to test the hypothesis that neutrophils fed CA-MRSA undergo necroptosis. Lysis of neutrophils fed CA-MRSA was independent of tumor necrosis factor α, active RIPK-1, and MLKL, but dependent on active RIPK-3. Human neutrophils fed CA-MRSA lacked phosphorylated RIPK-1, as well as phosphorylated or oligomerized MLKL. Neutrophils fed CA-MRSA possessed cytoplasmic complexes that included inactive caspase 8, RIPK-1, and RIPK-3, and the composition of the complex remained stable over time. Together, these data suggest that neutrophils fed CA-MRSA underwent a novel form of lytic programmed cell death via a mechanism that required RIPK-3 activity, but not active RIPK-1 or MLKL, and therefore was distinct from necroptosis. Targeting the molecular pathways that culminate in lysis of neutrophils during CA-MRSA infection may serve as a novel therapeutic intervention to limit the associated tissue damage.

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“…IFN-γ, similar to TGF-β, has been shown to stimulate the inflammatory phase of wound repair and improves phagocyte mediated activity against S. aureus. [55] In addition, there is evidence of cross-talk between TGF-β and IFN-γ, but IFN-γ reportedly delays wound healing, antagonizes the beneficial effects of TGF-β, and is associated with impaired wound healing in people and other animal models. [56,57] The role of IFN-γ specific to equine wound healing has not been extensively studied but, as with other species, the balance between pro-inflammatory IFN-γ and other cytokines is important and wound specific.…”

Section: Plos Onementioning

confidence: 99%

Effect of gallium maltolate on a model of chronic, infected equine distal limb wounds

et al. 2020

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Distal limb wounds are common injuries sustained by horses and their healing is fraught with complications due to equine anatomy, prevalence of infection, and challenges associated with wound management. Gallium is a semi-metallic element that has been shown to possess antimicrobial properties and aid in wound healing in various preclinical models. The effects of Gallium have not been studied in equine wound healing. Therefore, the objective of this study was to compare healing rates between gallium-treated and untreated wounds of equine distal limbs and to demonstrate the antimicrobial effects of gallium on wounds inoculated with S. aureus. Using an established model of equine wound healing we demonstrated beneficial effects of 0.5% topical gallium maltolate on equine wound healing. Specifically we documented reduced healing times, reduced bioburden, and reduced formation of exuberant granulation tissue in wounds treated with gallium maltolate as compared with untreated wounds. Gallium appeared to exert its beneficial effects via its well-described antimicrobial actions as well as by altering the expression of specific genes known to be involved in wound healing of horses and other animals. Specifically, gallium maltolate appeared to increase expression of transforming growth factor-β in both infected and uninfected wounds. Further work is needed to document the effects of gallium on naturally occurring equine wounds and to compare the effects of gallium with other wound treatment options. These data, however, suggest that gallium may be an attractive and novel means of improving equine distal limb wound healing.

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IFN-γ targets macrophage-mediated immune responses toward Staphylococcus aureus

Cited by 29 publications

References 47 publications

Inherited p40phox deficiency differs from classic chronic granulomatous disease

Inherited p40phox deficiency differs from classic chronic granulomatous disease

Lysis of human neutrophils by community-associated methicillin-resistant Staphylococcus aureus

Effect of gallium maltolate on a model of chronic, infected equine distal limb wounds

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