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Identifier 000444094
Title Metabolic regulation of macrophage activation
Alternative Title Μεταβολική ρύθμιση της ενεργοποίησης των μακροφάγων
Author Ξενικάκη, Ευσεβία
Thesis advisor Τσατσάνης, Χρήστος
Reviewer Κολλινιάτη, Ουρανία
Abstract Inflammation is the main protective mechanism of the immune system against any infection and injury. Macrophages are the central mediators of innate immune responses that maintain the integrity, homeostasis and balance in all tissues. They perform phagocytosis, antigen presentation and immunomodulation via various cytokines and growth factors production. Macrophages get activated by inflammatory signals recognized by Toll-like receptors (TLRs). Macrophage activation requires multiple layers of gene regulation leading to a vast spectrum of pro- or antiinflammatory phenotypes, termed as M1 or M2, respectively. This macrophage plasticity is regulated on epigenetic level, whereas different metabolic adaptations influence the outcome of inflammatory response. This present study aims to characterize the inflammatory status of macrophages lacking Akt1 or/and Akt2 kinases, upon different TLR-signaling. Moreover, we wanted to determine the epigenetic and metabolic state of Akt1- or/and Akt2-deficient macrophages after activation of different TLR-mediated inflammatory responses. For these purposes, primary peritoneal macrophages, which were collected by WT, LysMCreAkt1f/f, Akt2-/- and LysMCreAkt1f/f/Akt2f/f mice, were used in a series of experiments that addressed cell metabolism, epigenetic profile and inflammatory state basally and upon stimulation with TLR2, TLR4 and TLR7/8 ligands. The results showed that Akt1- or/and Akt2-deficient macrophages acquire different inflammatory status upon different TLR-activation. Particularly, Akt1/Akt2 KO macrophages responded more potently upon TLR4- and TLR7/8-signaling. Moreover, it was demonstrated that the absence of both Akt1 and Akt2 kinases upregulates at the basal levels a variety of epigenetic modifiers including PHF8, PHF2 and SIRT6. TLR4 and TLR7/8 signalling downregulated the PHF8 and PHF2 expression, which may be associated with the increased pro-inflammatory gene expression in Akt1/Akt2 KO macrophages. Furthermore, it was observed that Akt1- or/and Akt2-deficient macrophages demonstrated less metabolic activity (OXPHOS and glycolysis). Particularly, Akt1/Akt2 KO cells had reduced glycolysis and increased mitochondrial biogenesis at the naïve state, because of reduced HIF1a and increased pGC1a, respectively. Moreover, a possible association of reduced HIF1a with highly expressed SIRT6 was observed. The increased SIT6 possibly prevented the recruitment of HIF1a to its glycolysis-related target genes, resulting in reduced glycolysis of Akt1/Akt2 KO naïve cells. Upon TLR4 activation, macrophages lacking Akt1 or/and Akt2 consume all the available energy sources. After TLR7/8 stimulation, Akt1/Akt2 KO cells presented robust metabolic dysfunction, but they were able to meet their energy demands.
Language English
Subject TLR -signaling
TLR σηματοδότηση
ΑΚΤ κινάσες
Επιγενετική και μεταβολική ρύθμιση
Issue date 2021-12-01
Collection   School/Department--School of Medicine--Department of Medicine--Post-graduate theses
  Type of Work--Post-graduate theses
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