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    Overview

    Inflammation and inflammatory diseases are complex diseases implicating various cell types including these of the innate immune system. The magnitude and type of innate immune response is regulated by factors present in the cellular microenvironment and at the intracellular level.  

    Insulin is a pleiotropic hormone that signals in all cells including cells of the innate immune system. Insulin, when oscillates, acts as a negative regulator of inflammation, maintaining a balanced inflammatory response. Insulin activates PI3K/Akt signaling that suppress TLR-mediated signals reducing the magnitude of the inflammatory responses. Therefore, in macrophages, the central mediator of innate immune responses, insulin acts as a negative regulator of TLR signaling.

    Macrophages obtain distinct phenotypes that characterize the type and magnitude of the response to pathogenic and tissue damage signals. Such phenotypes are broadly described as being within the M1 or M2 polarization spectra, depending on whether they are hyper- or hypo-responsive to inflammatory signals. Evidence from our group has shown that Akt1 and Akt2 kinase isoforms differentially regulate macrophage responses controlling M1 and M2 polarization phenotypes (Vergadi et al, J Immunol, 2017, Vergadi et al, J. Immunol.2014, Arranz et al., PNAS, 2012 Androulidaki et al., Immunity, 2009).

    Recent evidence has shown that innate immune cells, including macrophages, develop memory, also known as trained immunity. Trained immunity is shaped by infectious signals present on pathogens, such as those initiated by Pathogen Associated Molecular Patterns (PAMPs), or by non-infectious signals such as modified lipoproteins (i.e. oxidized LDL). We have recently shown that insulin signaling shapes macrophage responses and insulin resistance is a state of trained immunity (Ieronymaki et al, J. Immunol. 2019; Ieronymaki et al, Front. Immunol. 2019). Our group is currently investigating the metabolic and epigenetic mechanisms initiated by insulin signaling and insulin resistance to result in this trained immunity state.

    Phagocytosis and autophagy is also altered in different states of trained immunity. Our group is currently studying the role of Akt kinases and insulin signaling in pathogen elimination through phagocytosis and autophagy. In addition, we are analyzing the differences between adult and neonatal macrophage responses in the context of phagocytosis and autophagy.

    Electron microscopy image of a macrophage engulfing bacteria

    Non-coding RNAs have also been implicated in controlling innate immune responses through Akt kinases (Androulidaki at al, Immunity. 2009; Vergadi et al, J Immunol. 2014) and among those, miRNAs have been established not only as regulators of innate immune responses but also as biomarkers of inflammation. Our group, in collaboration with the Department of Translational Medicine, Lund University Medical School, is analyzing the role of miRNAs and piRNAs as biomarkers of low grade systemic inflammation in patient cohorts (Trzybulska  et al, Cell Physiol Biochem. 2018; Vergadi et al, Front. Immunol. 2018; Kumar et al, Mol Cell Endocrinol. 2019).

    Inflammatory responses are also regulated by metabolites originating in the gut microbiome as well as by metabolites and small molecules made available through nutrition. Our group utilizes cell culture and mouse models of  inflammatory diseases such as obesity/type 2 diabetes, Inflammatory bowel disease, inflammation-induced intestinal tumorigenesis or skin inflammation, to understand the crosstalk of the gut microbiome, nutrition and metabolic products in macrophage responses and inflammation. Recent evidence from our group has shown that terpenes derived from the algae Laurencia promote M2-type of macrophage responses suppressing inflammatory bowel disease in mice (Daskalaki et al, Mar. Drugs. 2019).

     

    Our research aims in understanding the mechanisms controlling innate immune responses in the context of inflammatory, metabolic and infectious diseases.