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Identifier 000455591
Title Chemical and epigenetic regulation of macrophage activation and metabolism
Alternative Title Χημική και επιγενετική ρύθμιση της ενεργοποίησης και του μεταβολισμού των μακροφάγων
Author Δασκαλάκη, Μαρία
Thesis advisor Τσατσάνης, Χρήστος
Reviewer Καμπράνης, Σωτήρης
Καρδάσης, Δημήτρης
Βενυχάκη, Μαρία
Παπακωνσταντή, Ευαγγελία
Μερτσιάς, Γεώργιος
Χαραλαμπόπουλος, Ιωάννη
Abstract Inflammation is the first barrier against external and internal stimuli. It’s a multistep process including several complex mechanisms and driven by a great number of mediators and immune cells. Macrophages are effector cells of the immune system involved both in the initiation and resolution of inflammation that derive from monocyte precursors. They acquire an array of phenotypes broadly characterized as M1 and M2-like phenotypes. M1 macrophages express pro-inflammatory cytokines such as TNFa, IL-6 and IL-12 and secrete nitric oxide. On the other hand, M2 macrophages are involved in the resolution of inflammation and wound healing by expressing anti-inflammatory mediators such as Arginase1, MRC1, Fizz1 and Ym1. A broad spectrum of transcriptional regulatory programs such as the NF-kB and the MAPK/AKT signaling cascades ensure a well-coordinated inflammatory response. Tight coordination of the inflammatory response is pivotal for maintaining homeostasis as inflammatory dysregulation potentially results in the initiation of inflammation-related diseases such as autoimmunity, atherosclerosis and cancer. In the first part of this study, we screened for new chemical compounds with antiinflammatory properties deriving from the marine algae Laurencia glandulifera and Dictyopteris membranaceae. Having screened several compounds we showed that diterpenes 1-3 exhibited significant anti-inflammatory properties in RAW 264.7 macrophages inducing anti-inflammatory mediators’ production in naïve macrophages whereas reduced the production of pro-inflammatory cytokines in LPS activated macrophages. Diterpenes 1 and 3 exhibited the most potent anti-inflammatory properties with IC50 of 2.32μM and 2.92μM, respectively. Interestingly, diterpenes 2 and 3 managed to alleviate intestinal inflammation in a model of DSS induced colitis, reducing pro-inflammatory cytokine production and maintaining intestinal tissue integrity. Moreover, we showed that disulfides 4-6 deriving from D. membranaceae suppress macrophage activation in response to LPS stimulation by reducing pro-inflammatory cytokine production and this is mediated through the MAPK/AKT pathway exhibiting elevated AKT phosphorylation and diminished ERK1/2 phosphorylation. Then, we aimed to investigate the potential use of total dried algae Laurencia and Dictyopteris as dietary supplements and their potential role in alleviating inflammation related diseases. Indeed, we showed that diet supplementation with Laurencia or Dictyopteris reduced insulin resistance in high-fat induced obese mice and modulated the intestinal microbiome. Specifically, it not only maintained colonization of rare microbial taxa but also induced colonisation of beneficial bacteria in a sex-dependent manner. Using also a DSS-induced colitis model we showed that diet supplementation with Dictyopteris ameliorated the colitis phenotype in mice by reducing colon length shortening and proinflammatory cytokine and chemokine secretion. Although there is plenty of information on macrophage activation and polarization, little is known about the epigenetic regulation of the same processes. In the second part of the present study, we focus on investigating the role of histone demethylases PHF2 and PHF8 in macrophage activation and metabolism. First, we showed that PHF2 and PHF8 are differentially expressed upon TLR4-mediated activation indicating differential roles in macrophage activation. PHF2 expressed early (2h) upon LPS stimulation, whereas PHF8 expressed late (12h) following LPS stimulation, indicating a potential role in endotoxin tolerance. Then, we generated stable overexpressing and knock-out RAW 264.7 macrophages using a CRISPR-Cas9 lenti-viral system and studied their activation profile in response to LPS stimulation. We showed that PHF2 positively regulated pro-inflammatory gene production by actively binding on inflammatory gene promoters as well as it was necessary for the phagocytic capacity macrophages. On the contrary, PHF8 is a negative regulator of macrophage activation reducing pro-inflammatory gene expression in the context of endotoxin tolerance by actively binding on inflammatory gene promoters and positively regulates the phagocytic capacity of macrophages. In addition, PHF8 is a major regulator of metabolism during macrophage activation reducing major glycolytic genes and negatively regulating mitochondrial biogenesis and function. Specifically, PHF8 over expressing macrophages possess reduced mitochondrial mass and impaired mitochondrial function, exhibiting reduced ATP production and basal respiration capacity. Overall, this study adds to the current knowledge on macrophage activation and metabolism and proposes new chemical compounds as anti-inflammatory drugs with potential pharmaceutical interest in inflammatory responses. Moreover, it shades light into the field of the epigenetic regulation of innate immunity unravelling the major functions of histone demethylases PHF2 and PHF8 in macrophage activation and metabolism.
Language English
Subject Colitis
Cytokines
Demethylases
Dictyopteris
Disulfides
Diterpenes
Laurentia
Natural products
Obesity
Phagocytosis
Απομεθυλάσες
Δισουλφίδια
Διτερπενία
Κολίτιδα
Κυτοκίνες
Μακροφάγα
Μονοξείδιο του αζώτου
Παχυσαρκία
Φυσικά προϊόντα
Issue date 2023-07-28
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
Permanent Link https://elocus.lib.uoc.gr//dlib/4/7/5/metadata-dlib-1688638157-869857-14938.tkl Bookmark and Share
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