14 Chapter 1 located in the nucleus due to the absence of a nuclear export signal sequence. KDAC3, however, has a nuclear export signal and can be found in both the cytoplasmic and nuclear compartments. Class I KDACs are widely distributed in various tissues (64). Class II KDACs, divided into IIA (KDAC4, 5, 7, 9) and IIB (KDAC6, 10), can shuttle between the nucleus and cytoplasm in response to cellular signals (65). Sirtuins, the third group of KDACs, rely on NAD hydrolysis for their deacetylase activity and are located in different subcellular compartments. For example, SIRT1, SIRT6, and SIRT7 are found in the nucleus, SIRT2 is primarily cytosolic, and SIRT3–5 are located in mitochondria. Recent research has highlighted the role of sirtuins in connecting deacetylation with cellular metabolism, as deacetylation is responsive to metabolic cues (66). Additionally, KDAC11, the sole member of its class, shares similarities with both Class I and II KDACs. KDAC11 is involved in regulating the protein stability of DNA replication factor CDT1 (67) and negatively regulates the expression of interleukin 10, leading to an inflammatory response when overexpressed (68). KDAC inhibitors Lysine deacetylases (KDACs) are regulated by protein-protein interactions, posttranslational modifications, and subcellular localization. Dysregulation of KDACs is associated with various human diseases, leading to the development of KDAC inhibitors (KDACi) as therapeutic agents. Clinical trials have resulted in the approval of vorinostat and romidepsin for the treatment of cutaneous T-cell lymphoma (69). Classical KDACi act on Class I, II, and Class IV HDACs by binding to the zinc ion in the catalytic pocket. They inhibit deacetylation by preventing the binding of the natural substrate. On the other hand, romidepsin inhibits KDAC enzymatic activity by interacting with the zinc ion through its reduced disulfide bond (70). However, these inhibitors are not highly specific and can cause side effects. Newer KDACi, such as MS-275 (entinostat), based on a benzamide group as a Zn2+ binder, offer improved specificity. Class III KDACs, which are NAD+-dependent, can be inhibited by compounds like nicotinamide and derivatives of NAD (71). SCOPE OF THIS THESIS The work described in this thesis aimed to improve our understanding of the different phenotypes and functional properties of macrophages in chronic inflammation, specifically in the different tissue niches. Particular attention was paid to the role of metabolism in macrophage characterization.
RkJQdWJsaXNoZXIy MTk4NDMw