NOX2 Protects against Prolonged Inflammation, Lung Injury, and Mortality following Systemic Insults

Abstract

The systemic inflammatory response syndrome (SIRS) is a clinical condition occurring in intensive care unit patients as a consequence of both infectious and noninfectious insults. The mechanisms underlying resolution of SIRS are not well characterized. NOX2 (NADPH oxidase 2)-derived reactive oxygen species are critical for killing of certain pathogens by polymorphonuclear leukocytes (PMN). Patients with chronic granulomatous disease who lack functional NOX2 are not only prone to serious infections, they also exhibit chronic inflammatory conditions, suggesting a local anti-inflammatory role for NOX2. We hypothesized that NOX2 is required for the resolution of sterile systemic inflammation. Using a murine model of sterile generalized inflammation, we observed dramatically increased mortality of gp91^phox-/y (NOX2-deficient) as compared to wild-type (WT) mice. Both genotypes developed robust SIRS with hypothermia, hypotension, and leukopenia; however, WT mice recovered within 48 h whereas NOX2-deficient mice did not. Although both groups displayed rapid peritoneal PMN recruitment, the recruited NOX2-deficient PMN demonstrated an enhanced inflammatory phenotype. Moreover, NOX2-deficient mice exhibited a hemorrhagic inflammatory response in the lungs with rapid and persistent recruitment of neutrophils to the alveolar space, whereas WT mice had minimal lung pathology. Several proinflammatory cytokines remained elevated in NOX2-deficient mice. The persistent inflammatory environment observed in NOX2-deficient mice resulted from continued peritoneal chemokine secretion and not delayed apoptosis of PMN. These data suggest a requirement for NOX2 in the resolution of systemic inflammation.

Bimodal role of NADPH oxidases in the regulation of biglycan-triggered IL-1β synthesis

“…This is in agreement with the previous findings that NOX2 deficiency in mice leads to increased levels of IL-1β in the early onset of arthritis and therefore to a more severe inflammatory phenotype [35]. Moreover, NOX2-derived ROS is essential for the phagosome function and it has been considered as a barrier of sustained inflammation [56][57][58]. Hence, we hypothesize that this protective role of NOX2-generated ROS in inflammation and IL-1β production could be regulated by biglycan.…”

NADPH Oxidase Deficiency Exacerbates Angiotensin II–Induced Abdominal Aortic Aneurysms in Mice

“…Because an absence of Nox2 has been found to upregulate proinflammatory responses (eg, production of IL-1β, IL-6 , and TNF-α), thereby aggravating arthritis 18 and systemic inflammatory response syndrome, 19 as well as chronic granulomatous disease, 15 Nox2 may possess anti-inflammatory-like effects even in inflammatory vascular diseases. Consistent with previous findings, 20 we found that NOX2 contributes to reactive oxygen species generation in macrophages, although we also found that a Nox2 deficiency in macrophages potentiated the secretion of IL-1β and MMP9.…”

A Common Genetic Variant in TLR1 Enhances Human Neutrophil Priming and Impacts Length of Intensive Care Stay in Pediatric Sepsis

“…Our laboratory became interested in neutrophil responses to TLR2 agonists after finding complex and unexpected interactions between TLR2 ligation and the NADPH oxidase 2 using a murine model of systemic inflammation elicited by injection of a TLR2 agonist (15, 16). In the current study, we sought to further define human PMN priming responses to TLR2 ligands in vitro/ex vivo .…”