Department of Chemical and Pharmaceutical Biology, Groningen, Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
Published: October 2023
AI Article Synopsis
Article Abstract
Macrophage polarization plays a crucial role in inflammatory processes. The histone deacetylase 3 (HDAC3) has a deacetylase-independent function that can activate pro-inflammatory gene expression in lipopolysaccharide-stimulated M1-like macrophages and cannot be blocked by traditional small-molecule HDAC3 inhibitors. Here we employed the proteolysis targeting chimera (PROTAC) technology to target the deacetylase-independent function of HDAC3. We developed a potent and selective HDAC3-directed PROTAC, P7, which induces nearly complete HDAC3 degradation at low micromolar concentrations in both THP-1 cells and human primary macrophages. P7 increases the anti-inflammatory cytokine secretion in THP-1-derived M1-like macrophages. Importantly, P7 decreases the secretion of pro-inflammatory cytokines in M1-like macrophages derived from human primary macrophages. This can be explained by the observed inhibition of macrophage polarization from M0-like into M1-like macrophage. In conclusion, we demonstrate that the HDAC3-directed PROTAC P7 has anti-inflammatory activity and blocks macrophage polarization, demonstrating that this molecular mechanism can be targeted with small molecule therapeutics.
Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, P. R. China.
The potassium channel Kv1.3 plays an important role in regulating immune cell functions in many inflammatory diseases whereas rarely in osteoarthritis (OA). Here, it is demonstrated that the Kv1.
Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Periodontics, Shanghai Tongji Stomatological Hospital and Dental School, Tongji University, Shanghai 200072, China.
Periodontitis is a chronic inflammatory disease influenced by macrophage polarization. Additionally, succinylation-enriched Porphyromonas gingivalis is a pathogenic factor of periodontitis. However, the role of succinylation in the pathogenesis of periodontitis remains unclear.
Background: Osteoarthritis (OA) is a painful degenerative joint disease and a leading source of years lived with disability globally due to inadequate treatment options. Neuroimmune interactions reportedly contribute to OA pain pathogenesis. Notably, in rodents, macrophages in the DRG are associated with onset of persistent OA pain.
Introduction: Macrophages exist on a spectrum from pro-inflammatory (M1) to pro-healing (M2). Characterization of macrophage phenotype is important to understand tissue healing and response. The gold standard for assessing macrophage phenotypes is immunocytochemistry (ICC), which stains inducible Nitric Oxide Synthase (iNOS) and arginase (Arg1), the proteins secreted before nitrite and urea production.
Background: Adipose-derived stem cells (ADSCs) are widely used in the field of regenerative medicine because of their various functions, including anti-inflammatory effects. ADSCs are considered to exert their anti-inflammatory effects by secreting anti-inflammatory cytokines and extracellular vesicles. Although recent studies have reported that metabolites have a variety of physiological activities, whether those secreted by ADSCs have anti-inflammatory properties remains unclear.
