Caspase Inhibition Modulates Monocyte-Derived Macrophage Polarization in Damaged Tissues

• Published in: International journal of molecular sciences 2023-02, Vol.24 (4), p.4151
• Main Authors: Solier, Stéphanie, Mondini, Michele, Meziani, Lydia, Jacquel, Arnaud, Lacout, Catherine, Berghe, Tom Vanden, Julé, Yvon, Martinou, Jean-Claude, Pierron, Gérard, Rivière, Julie, Deloger, Marc, Dupuy, Corinne, Slama-Schwok, Anny, Droin, Nathalie, Vandenabeele, Peter, Auberger, Patrick, Deutsch, Eric, El-Benna, Jamel, Dang, Pham My-Chan, Solary, Eric
• Format: Article
• Language: English
• Subjects: Adenine; Animals; Anions; Apoptosis; Bleomycin; Caspase 7 - metabolism; Caspase-3; Caspase-7; Caspases - metabolism; Chronic granulomatous disease; Colony-stimulating factor; CYBB protein; Cytoplasm; Enzymes; Fibrosis; Genotype & phenotype; Humans; Kinases; Life Sciences; Macrophage colony-stimulating factor; Macrophage Colony-Stimulating Factor - metabolism; Macrophages; Macrophages - metabolism; Mice; Microscopy; Mitochondria; Monocytes; Monocytes - metabolism; NAD(P)H oxidase; NADPH Oxidases - metabolism; NADPH-diaphorase; Niacinamide; Nicotinamide; Oxidases; Polarization; Proteins; Reactive Oxygen Species - metabolism; Scavenging; Scientific equipment and supplies industry; Superoxide; Superoxide anions
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24044151

Circulating monocytes are recruited in damaged tissues to generate macrophages that modulate disease progression. Colony-stimulating factor-1 (CSF-1) promotes the generation of monocyte-derived macrophages, which involves caspase activation. Here, we demonstrate that activated caspase-3 and caspase-7 are located to the vicinity of the mitochondria in CSF1-treated human monocytes. Active caspase-7 cleaves p47 at aspartate 34, which promotes the formation of the NADPH (nicotinamide adenine dinucleotide phosphate) oxidase complex NOX2 and the production of cytosolic superoxide anions. Monocyte response to CSF-1 is altered in patients with a chronic granulomatous disease, which are constitutively defective in NOX2. Both caspase-7 down-regulation and radical oxygen species scavenging decrease the migration of CSF-1-induced macrophages. Inhibition or deletion of caspases prevents the development of lung fibrosis in mice exposed to bleomycin. Altogether, a non-conventional pathway that involves caspases and activates NOX2 is involved in CSF1-driven monocyte differentiation and could be therapeutically targeted to modulate macrophage polarization in damaged tissues.