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Identifier 000416978
Title Regulation of inflammation in obesity
Alternative Title Μηχανισμοί ρύθμισης της φλεγμονής κατά την παχυσαρκία
Author Λυρώνη, Κωνσταντίνα
Thesis advisor Τσατσάνης, Χρήστος
Reviewer Μαργιωρής, Ανδρέας
Καρδάσης, Δημήτριος
Νότας, Γεώργιος
Ηλιόπουλος, Αριστείδης
Παπακωνσταντή, Ευαγγελία
Βενυχάκη, Μαρία
Μπερτσιάς, Γεώργιος
Abstract Inflammation underlies a variety of physiological and pathological processes. Over the years tremendous progress has been made in understanding the cellular and molecular events that are involved in inflammatory responses. A controlled inflammatory response is beneficial for the organism in order to maintain homeostasis, protect from infection and repair tissue damage, but it can also become detrimental if not regulated appropriately. Different instigators of inflammation, such as infection and tissue injury, are among the wide spectrum of adverse conditions that induce inflammation. In chronic inflammatory diseases such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Diseases and others, pathogenesis occurs due to excessive, inappropriately initiated inflammatory response. Metabolic diseases such as obesity and type II diabetes are also characterized by chronic, low-grade inflammation that has led to the concept of metabolic inflammation (metaflammation). Despite the fact that mechanisms of inflammatory response have been extensively studied, further elucidating the molecular controls of inflammation is of crucial importance. Macrophages are key players in inflammation activated by a wide spectrum of stimuli and acquire a phenotype that ranges from fully pro-inflammatory (M1) to anti-inflammatory, mediating resolution of inflammation and tissue repair (M2). Metabolic inflammation results in changes in macrophage phenotype as well. Inflammed adipose tissue has an increased number of macrophages and these macrophages are pro-inflammatory (M1-type). Effective termination of inflammation is as important as controlled initiation, therefore a plethora of factors exist that act as negative regulators. TLR signaling contributes to inflammation and metaflammation and is negatively regulated by the IL-1 Receptor Associated Kinase M (IRAK-M) protein, which acts as 12 | P a g e functional decoy to prevent phosphorylation and further signaling by IRAK-4. The world-wide epidemic of obesity has led to a dramatic increase in metabolic diseases associated with metabolic inflammation, hence deciphering the mechanisms governing processes that establish metaflammation, will allow understanding the pathogenesis of related conditions. Adipocytes are now acknowledged as more than cells for lipid storage. They have primary roles in controlling energy homeostasis and secrete hormones and lipids in order to regulate systemic metabolism. Adipose tissue is in a state of inflammation in obesity contributing to low grade systemic inflammation. Given the established importance of inflammation and metabolism in health and disease, the present study focused on analyzing the transcriptional and epigenetic mechanisms of macrophage activation focusing on the mechanisms of regulation of the intracellular TLR-signaling modulator IRAK-M (a negative regulator of the TLR4/LPS signaling). The work also aimed to decipher whether adipocytes can acquire a macrophage-like phenotype in states of inflammation such as obesity and LPS stimulation and how this is be regulated. Using high-throughput targeted siRNA knock-down of genes that are known transcription factors, signaling molecules and epigenetic regulators in macrophages ones affecting IRAK-M activation by LPS were identified. Molecules that had the strongest effect in either up-regulating or down-regulating IRAK-M expression were selected for further validation. The transcription factor C/EBPβ was identified as a transcriptional activator of the IRAK-M gene upon LPS stimulation of macrophages. ChIP experiments showed that C/EBPβ is recruited to IRAK-M promoter shortly after LPS stimulation to activate its transcription. Additional ChIP experiments showed that NFκΒ/p65 and NFκΒ/RelB were also recruited to IRAK-M promoter shortly after 13 | P a g e C/EBPβ to maintain transcription active. In addition to transcription factors, epigenetic regulators are also key players in the regulation of gene transcription. Targeted siRNA knock-down of EZH2, the PRC2 complex methyl-transferase, as well as stable shRNA expression experiments showed that IRAK-M gene transcription was regulated by this protein upon LPS activation. In parallel, we studied inflammatory responses in adipocytes using Mouse Embryonic Fibroblasts that were differentiated to mature adipocytes as well as primary adipocytes from lean and obese mice. Cells were activated with LPS and their phenotype was analyzed. Results showed that adipocytes acquired an inflammatory phenotype resembling the one observed in macrophages when activated by LPS. Using gene knock-out animals we found that osteopontin regulated inflammatory activation of adipocytes. Ablation of OPN resulted in increased activation of adipocytes since OPN-deficient adipocytes secreted more TNFα, induced higher levels of iNOS producing more nitrites. This effect was found to be mediated by PPARγ and probably independent of LPS-TLR4 signaling. Overall, this study adds to the current knowledge of the regulation of inflammation and metabolic inflammation by deciphering a mechanism of IRAK-M gene transcription and by elucidating a new factor that mediates inflammatory response in adipocytes.
Language English
Subject IRAK-M
Issue date 2018-07-18
Collection   Faculty/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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