Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages

• DOI: 10.1016/j.redox.2022.102591
• Publication Date: 2022-12-24T12:14:50Z
• Authors: Sjors Maassen; Britt Coenen; Melina Ioannidis; Karl Harber; Pieter Grijpstra; Jan Van den Bossche; Geert van den Bog...
• Keywords: Lipopolysaccharides; Inflammation; Medicine (General); 0303 health sciences; QH301-705.5; Tumor Necrosis Factor-alpha; Macrophages; 3. Good health; 03 medical and health sciences; R5-920; Phenotype; Cyclooxygenase 2; Transforming Growth Factor beta; Humans; Collagen; Biology (General); Research Paper

Pathological conditions associated with dysfunctional wound healing are characterized by impaired remodelling of extracellular matrix (ECM), increased macrophage infiltration, and chronic inflammation. Macrophages also play an important role in as they drive closure secretion molecules like transforming growth factor beta-1 (TGF-β). As the functions macrophages regulated their metabolism, local administration small that alter this might be a novel approach for treatment wound-healing disorders. Itaconate is tricarboxylic acid (TCA) cycle-derived metabolite has been resolution macrophage-mediated However, its effects on unknown. In study, we investigated membrane-permeable 4-octyl itaconate (4-OI) derivative ECM scavenging cultured human blood monocyte-derived (hMDM). We found 4-OI reduced signalling p38 mitogen-activated protein kinase (MAPK) induced canonical immune stimulus lipopolysaccharide (LPS). Likely consequence this, production inflammatory mediators tumor necrosis (TNF)-α cyclooxygenase (COX)-2 were reduced. On transcriptional level, expression gene coding TGF-β (TGFB1), whereas collagenase metalloprotease-8 (MMP8) was Furthermore, surface levels anti-inflammatory marker CD36, but not CD206 CD11c, these cells. To directly investigate effect macrophages, developed assay to measure uptake fibrous collagen. observed LPS promoted collagen reversed 4-OI-induced signaling nuclear erythroid 2-related 2 (NRF2), regulator cellular resistance oxidative stress glycolytic capacity macrophage. These results indicate lowers inflammation, likely promoting more wound-resolving phenotype.