Mechanisms of CO2‐dependent regulation of NFκB signaling

Abstract

Carbon dioxide (CO2) is a physiological gas produced as a by‐product of oxidative metabolism. Physiologically, CO2 levels within the blood of respiring animals are significantly higher than the external environment at approximately 35mmHg or 5% CO2. This creates a CO2 gradient around respiring organisms that many species have evolved the ability to sense. For instance, mosquitos sense the CO2 gradient around organisms in order to locate a blood meal. However, while CO2 is acutely sensed via chemosensitive neurons, CO2 also impacts on a transcriptional level. Notably, studies in Drosophila have demonstrated that flies exposed to hypercapnia (elevated CO2) have significantly increased infection‐induced mortality due to down‐regulation of multiple Rel‐dependent genes. These genes code for anti‐microbial peptides which are key immune effectors regulated by an NFκB orthologue Relish. In humans, hypercapnia is a feature of many lung pathologies such as chronic obstructive pulmonary disease (COPD) and is associated with a poor prognosis in these patients at least in part due to their susceptibility to infection. Thus, the current state of the art is that hypercapnia is detrimental in the context of infection due to immunosuppression. Interestingly however, recent studies suggest that exploiting the anti‐inflammatory effects of CO2 might be of benefit clinically e.g. during one lung ventilation. Importantly, the mechanisms of action for these effects are poorly understood. Thus, the aim of this project is to gain novel, mechanistic insight into CO2‐dependent alterations of NFκB signalling and inflammatory gene expression.In our previously published work we have shown that in the absence of an inflammatory stimulus, hypercapnia results in altered RelB processing, nuclear translocation and protein‐protein interaction (particularly those in DNA binding). Furthermore, several other members of the non‐canonical NFκB family such as IKKα and p100 also undergo cellular re‐localisation. Here we investigate the effect of hypercapnia on inflammatory signalling against the background of an immune stimulus and determine the relative contribution of key NFkB proteins in the response. In the stimulated state (cells treated with lipopolysaccharide (LPS)), we show using a cytokine array that hypercapnia alters inflammatory cytokine expression. Our data indicates that against a background of immune stimulation hypercapnia can alter both canonical (p65) and non‐canonical (RelB) NFκB‐regulated cytokines. Taken together, this study gives exciting, novel mechanistic insight into the effects of CO2 on NFκB‐dependent inflammatory signaling which is of clinical relevance for patients who experience elevated levels of CO2.Support or Funding InformationFunded by UCD School of Medicine and Science Foundation Ireland (15/CDA/3490)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.