Linking cellular metabolism and Innate Defence Regulator peptide function

Appropriate cellular metabolism is essential to immune cells to survival and their ability to mount effective and appropriate responses to the pathogen and host derived insults they encounter. Malnutrition, caused by nutrient deficiency or excess, can result in significant dysregulation of immune cell activity. Immune cells undergo metabolic reprogramming in response to pathogen and host-derived signals found in their environment. These changes modulate the type of response they will mount. Innate defence regulatory (IDR) peptides, synthetic derivatives of host defence peptides, were developed as anti-infectives that modulate host immune system responses however, much of the mechanisms behind their activity are unknown. In this study, IDR-1018 was shown to modulate glycolytic activity in macrophages, which appeared to be important to its immunomodulatory activity. Activation of the ERK signalling pathway, a major regulator of metabolism and inflammatory responses, by IDR-1018 was found to be a possible mechanism by which IDR-1018 induced both glycolysis and chemokine production. Inhibition of glycolysis using 2-deoxy-d-glucose (2DG) suppressed IDR-1018 induced chemokine production. However, 2DG also suppressed IDR-1018 activity through induction of endoplasmic reticulum stress and the unfolded protein response (UPR), specifically the anti-inflammatory PERK arm of the UPR. The anti-endotoxin activity of IDR-1018 was also found to be associated with modulation of glycolysis. IDR-1018 suppressed lipopolysaccharide (LPS)-induced chemokine and cytokine production, possibly through inhibition of LPS-induced glycolysis. Interestingly, dysregulation of both glycolysis and the UPR by 2DG enhanced the anti-endotoxin activity of IDR-1018, suppressing LPS-induced chemokine and cytokine production. Finally, this study identified a potential new activity for IDRs, the modulation of metabolic pathways dysregulated in response to nutrient excess. Specifically, this study showed that IDR-1018 enhanced HDL-mediated cholesterol efflux from macrophages and smooth muscle cells, two important cellular mediators of atherosclerosis. This may have been a result of IDR-1018 interacting with HDL particles found in serum, facilitating their binding to the plasma membrane of cells. The results presented in this study demonstrated that IDR peptides are potent modulators of both immune cell function and cellular metabolism as well as identified a novel mechanism by which IDR peptides exert their immunomodulatory activity.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat