Female X-Chromosome Mosaicism for NOX2 Deficiency Presents Unique Inflammatory Phenotype and Improves Outcome in Polymicrobial Sepsis

Chandra, Rachna; Federici, Stephanie; Németh, Zoltán; Horváth, Béla; Pacher, Pál; Haskó, György; Deitch, Edwin A.; Spolarics, Zoltán

doi:10.4049/jimmunol.1100205

Cited by 26 publications

(24 citation statements)

References 38 publications

(31 reference statements)

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“…Gp91 phox expression in neutrophils was assessed with an anti-mouse gp91 phox mAb (BD Biosciences) (22). Briefly, after staining for neutrophils with FITC-conjugated anti-mouse Ly6G mAb and PE-Cy7-conjugated anti-mouse CD11b mAb, cells in suspension were fixed with 2% paraformaldehyde for 20 min.…”

Section: Methodsmentioning

confidence: 99%

Influenza Infection Suppresses NADPH Oxidase–Dependent Phagocytic Bacterial Clearance and Enhances Susceptibility to Secondary Methicillin-Resistant Staphylococcus aureus Infection

Sun

Metzger

2014

The Journal of Immunology

103

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Methicillin-resistant S. aureus (MRSA) has emerged as a leading contributor to mortality during recent influenza pandemics. The mechanism for this influenza-induced susceptibility to secondary S. aureus infection is poorly understood. Here we show that innate antibacterial immunity was significantly suppressed during the recovery stage of influenza infection, despite the fact that MRSA super-infection had no significant effect on viral burdens. Compared to mice infected with bacteria alone, post-influenza MRSA infected mice exhibited impaired bacterial clearance, which was not due to defective phagocyte recruitment, but rather coincided with reduced intracellular reactive oxygen species (ROS) levels in alveolar macrophages and neutrophils. NADPH oxidase is responsible for ROS production during phagocytic bacterial killing, a process also known as oxidative burst. We found that gp91phox-containing NADPH oxidase activity in macrophages and neutrophils was essential for optimal bacterial clearance during respiratory MRSA infections. In contrast to WT animals, gp91phox−/− mice exhibited similar defects in MRSA clearance before and after influenza infection. Using gp91phox+/− mosaic mice, we further demonstrate that influenza infection inhibits a cell-intrinsic contribution of NADPH oxidase to phagocyte bactericidal activity. Together, our results establish that influenza infection suppresses NADPH oxidase-dependent bacterial clearance and leads to susceptibility to secondary MRSA infection.

show abstract

Section: Methodsmentioning

confidence: 99%

Influenza Infection Suppresses NADPH Oxidase–Dependent Phagocytic Bacterial Clearance and Enhances Susceptibility to Secondary Methicillin-Resistant Staphylococcus aureus Infection

Sun

Metzger

2014

The Journal of Immunology

103

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“…On the day of the sacrifice, blood was immediately collected and serum levels of creatinine and Blood Urea Nitrogen (BUN) were measured using VetTest 8000 blood chemistry analyzer (Idexx Lab)[29]. …”

Section: Methodsmentioning

confidence: 99%

β-Caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner

Horváth

Mukhopadhyay

Kechrid

et al. 2012

Free Radical Biology and Medicine

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117

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(E)-β-caryophyllene (BCP) is a natural sequiterpene found in many essential oils of spice (best known for contributing to the spiciness of black pepper) and food plants with recognized anti-inflammatory properties. Recently it was shown that BCP is a natural agonist of endogenous cannabinoid 2 (CB2) receptors, which are expressed in immune cells and mediate anti-inflammatory effects. In this study we aimed to test the effects of BCP in a clinically relevant murine model of nephropathy (induced by the widely used antineoplastic drug cisplatin) in which the tubular injury is largely dependent on inflammation and oxidative/nitrative stress. β-caryophyllene dose-dependently ameliorated cisplatin-induced kidney dysfunction, morphological damage, and renal inflammatory response (chemokines MCP-1 and MIP-2, cytokines TNF-α and IL-1β, adhesion molecule ICAM-1, and neutrophil and macrophage infiltration). It also markedly mitigated oxidative/nitrative stress (NOX-2, NOX-4 expression, 4-HNE and 3-NT content) and cell death. The protective effects of BCP against biochemical and histological markers of nephropathy were absent in CB2 knockout mice. Thus, BCP may be an excellent therapeutic agent to prevent cisplatin-induced nephrotoxicity through a CB2 receptor dependent pathway. Given the excellent safety profile of BCP in humans it has tremendous therapeutic potential in multitude of diseases associated with inflammation and oxidative stress.

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“…Polymicrobial septic peritonitis was induced using the cecal ligation and puncture (CLP) model as described earlier (20,21). Briefly, animals were anesthetized by an ip injection of Nembutal (5mg/100g bw).…”

Section: Methodsmentioning

confidence: 99%

IRAK1-Dependent Signaling Mediates Mortality in Polymicrobial Sepsis

Chandra¹,

Federici²,

Bishwas³

et al. 2013

Inflammation

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IRAK1 is a key regulatory protein in TLR/IL1R-mediated cell activation during the inflammatory response. Studies indicated that pending on the nature of the used inflammatory model, down-regulation of IRAK1 may be beneficial or detrimental. However the role of IRAK1 in affecting outcome in polymicrobial sepsis is unknown. We tested this question using an IRAK1 deficient mouse strain and the cecal ligation and puncture (CLP) procedure, which is a clinically relevant rodent septic model. Sepsis-induced mortality was markedly lower in IRAK1-deficient mice (35%) compared to WT (85%). Sepsis-induced increases in blood IL-6 and IL-10 levels were blunted at 6h post-CLP in IRAK1 deficiency compared to WT but cytokine levels were similar at 20h post-CLP. Sepsis induced blood granulocytosis and depletion of splenic B cells were also blunted in IRAK1 deficient mice as compared to WT. Analysis of TLR-mediated cytokine responses by IRAK1 deficient and WT macrophages ex vivo indicated a TLR4-dependent down-regulation of IL-6 and IL1β in IRAK1 deficiency, whereas TLR2 dependent responses were unaffected. TLR7/8-mediated IL-6, IL1β and IL-10 production was also blunted in IRAK1 macrophages as compared to WT. The study shows that IRAK1 deficiency impacts multiple TLR-dependent pathways and decreases early cytokine responses following polymicrobial sepsis. The delayed inflammatory response caused by the lack of IRAK1 expression is beneficial, as it manifests a markedly increased chance of survival after polymicrobial sepsis.

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Female X-Chromosome Mosaicism for NOX2 Deficiency Presents Unique Inflammatory Phenotype and Improves Outcome in Polymicrobial Sepsis

Cited by 26 publications

References 38 publications

Influenza Infection Suppresses NADPH Oxidase–Dependent Phagocytic Bacterial Clearance and Enhances Susceptibility to Secondary Methicillin-Resistant Staphylococcus aureus Infection

Influenza Infection Suppresses NADPH Oxidase–Dependent Phagocytic Bacterial Clearance and Enhances Susceptibility to Secondary Methicillin-Resistant Staphylococcus aureus Infection

β-Caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner

IRAK1-Dependent Signaling Mediates Mortality in Polymicrobial Sepsis

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