8-Oxoguanine-DNA glycosylase 1 deficiency modifies allergic airway inflammation by regulating STAT6 and IL-4 in cells and in mice

Abstract

8-oxoguanine-DNA glycosylase (OGG-1) is a base excision DNA repair enzyme; however, its function in modulating allergic diseases remains undefined. Using OGG-1 knockout (KO) mice, we show that this protein impacts allergic airway inflammation following sensitization and challenge by ovalbumin (OVA). OGG-1 KO mice exhibited less inflammatory cell infiltration and reduced oxidative stress in the lungs after OVA challenge compared to WT mice. The KO phenotype included decreased IL-4, IL-6, IL-10, and IL-17 in lung tissues. In addition, OGG-1 KO mice showed decreased expression and phosphorylation of STAT6 as well as NF-κB. Down-regulation of OGG-1 by siRNA lowered ROS and IL-4 levels but increased INF-γ production in cultured epithelial cells following exposure to house dust mite (HDM) extracts. OGG-1 may affect the levels of oxidative stress and proinflammatory cytokines during asthmatic conditions. OGG-1-deficiency negatively regulates allergen-induced airway inflammatory response.

Neil2-null Mice Accumulate Oxidized DNA Bases in the Transcriptionally Active Sequences of the Genome and Are Susceptible to Innate Inflammation

“…Furthermore, we found a higher frequency (Fig. 6B, compare Increased Susceptibility of Neil2-null Mice to InflammationPrevious reports have indicated that Ogg1-null mice have decreased susceptibility to LPS-induced and oxidative stressinduced inflammation (44,45) and also to allergic immune responses (46,47). To address the susceptibility of Neil2-null mice to inflammation, animals were challenged intranasally with LPS (100 ng/per lung) or TNF-␣ (20 ng/lung) or GOx (1 milliunit/lung).…”

The R213G polymorphism in SOD3 protects against allergic airway inflammation

“…(42)(43)(44)(45)(46)(47). Allergic asthma, oxidative stress, and lung inflammation go hand-in-hand (48,49). There are reports suggesting that EC-SOD plays a major role in determining the progression of allergic lung disease by controlling DC maturation and T lymphocyte priming, differentiation, proliferation, and activation (25).…”

Innate Inflammation Induced by the 8-Oxoguanine DNA Glycosylase-1–KRAS–NF-κB Pathway

“…Mabley and colleagues showed that that Ogg 1-null mice are resistant to endotoxin (LPS)-induced organ dysfunction, neutrophil infiltration, and oxidative stress compared to the response seen in wild-type controls (12). In another study, sensitized Ogg 1-null mice exhibited lower IL-4, IL-6, IL-10, and IL-17 production and decreased levels of inflammatory cell infiltration and oxidative stress in the lungs after ovalbumin challenge compared to levels in wild-type controls (13). Bacsi and colleagues showed that supraphysiological levels of 8-oxoG in the genome of the airway epithelium (AE) due to decreased OGG1 expression evoked a lower inflammatory response in challenged-sensitized mice, as determined by expression of Th2 cytokines, eosinophilia, epithelial metaplasia, and airway hyperresponsiveness (AHR) (14).…”