1. Metabolic and epigenetic mechanisms regulating macrophage responses; the role of insulin signaling and Akt kinases.
We have recently shown that macrophages become insulin resistance and obtain an M2-like phenotype with distinct TLR responses, describing a state of trained immunity (Ieronymaki et al, J. Immunol. 2019; Ieronymaki et al, Front. Immunol. 2019). We are currently investigating the epigenetic mechanisms involved in macrophage training in the context of either genetically-induced insulin resistance (Akt2 deficient or IGF1R deficient macrophages) or macrophages derived from diet-induced insulin resistant mice. The interplay between epigenetic alterations at the level of histone modifications and cell metabolism is being investigated. The role of autophagy and phagocytosis in the context of insulin resistance-trained macrophages is also analyzed.
2. Regulation of macrophage responses in the context of critical illness and sepsis and the role of insulin signaling (in collaboration with Associate Prof. K. Vaporidi, Univ. of Crete).
Critically ill and septic patients enter a state of trained immunity, also characterized as endotoxin tolerance or immunoparalysis. We have previously shown that Akt kinases and miRNAs play a key role in regulating endotoxin tolerance (Androulidaki et al, Immunity 2009; Doxaki et al, J Immunol. 2015, Vergadi et al, Front. Immunol. 2018). Insulin is continuously infused in critically ill patients and insulin oscillation is abolished. We are currently investigating the contribution of insulin oscillatory signaling and insulin resistance in regulating macrophage responses and immunoparalysis, using mouse models and ex-vivo studies from patient samples.
3. Understanding differences between adult and neonatal innate immune responses (in collaboration with Assistant Prof. E. Vergadi, Dept. of Pediatrics Univ. of Crete, Prof. T. Chavakis, TU Dresden, Prof. G. Hajishengallis, Univ. of Pennsylvania).
Newborns rely on innate immunity to combat pathogens prior to maturation of the adaptive immune system, yet innate immune responses are still immature and not always effective. Thus, neutrophil recruitment at the site of inflammation is not efficient and the capacity of neonatal macrophages to eliminate bacteria is not as efficient as it is in adult cells. We are currently investigating differences between adult and neonatal innate immune responses in the context of neutrophil recruitment and the role of Del-1 protein during polymicrobial sepsis. We are also studying the role of autophagy as a mechanism of pathogen clearance in neonates and the role of Akt kinases in this context.
4. The crosstalk of gut microbiome and innate immune responses and the role of dietary and metabolic products (in collaboration with Associate Prof. M. Venihaki).
It is widely acknowledged that the gut microbiome affects innate immune responses in the context of metabolic and inflammatory diseases. Our group analyzes the impact of insulin resistance-trained macrophages in shaping the gut microbiome using mice carrying genetically-induced insulin resistant macrophages. We are also studying the impact of nutritional products and metabolites in shaping the gut microbiome and how these can affect macrophage responses and the development of inflammatory diseases. We have recently identified algae-derived terpenes and other molecules having potent anti-inflammatory activity. We have developed a cell culture platform utilizing adipocytes and macrophages, for screening isolated compounds or extracts from marine organisms and validate those in in vivo models of inflammatory diseases (obesity/type 2 diabetes, inflammatory bowel disease, skin inflammation and other) to identify potential bioactive molecules or extracts.