Effects of thrombospondin-4 on pro-inflammatory phenotype differentiation and apoptosis in macrophages

• Published in: Cell death & disease 2020-01, Vol.11 (1), p.53-53, Article 53
• Main Authors: Rahman, Mohammed Tanjimur, Muppala, Santoshi, Wu, Jiahui, Krukovets, Irene, Solovjev, Dmitry, Verbovetskiy, Dmitriy, Obiako, Chioma, Plow, Edward F., Stenina-Adognravi, Olga
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/51; 38/77; 64/60; 692/308/2778; 692/420/256; 82/29; 82/80; 96/2; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Arteriosclerosis; Atherosclerosis; Biochemistry; Biomarkers - metabolism; Biomedical and Life Sciences; Cardiovascular diseases; Cell Biology; Cell Culture; Cell Survival - drug effects; Cytokines - metabolism; Genotype & phenotype; Granulocyte-macrophage colony-stimulating factor; Immunology; Inflammation; Inflammation - pathology; Inflammation Mediators - metabolism; Leukocyte migration; Life Sciences; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Macrophages; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - metabolism; Macrophages, Peritoneal - pathology; Mice; Mice, Inbred C57BL; Monocytes - drug effects; Monocytes - pathology; Peritoneum; Peritonitis; Peritonitis - pathology; Phenotype; Phenotypes; Phosphorylation - drug effects; Population studies; RAW 264.7 Cells; Recombinant Proteins - pharmacology; Thrombospondin; Thrombospondins - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-2237-2

Thrombospondin-4 (TSP-4) attracted renewed attention recently as a result of assignment of new functions to this matricellular protein in cardiovascular, muscular, and nervous systems. We have previously reported that TSP-4 promotes local vascular inflammation in a mouse atherosclerosis model. A common variant of TSP-4, P387-TSP-4, was associated with increased cardiovascular disease risk in human population studies. In a mouse atherosclerosis model, TSP-4 had profound effect on accumulation of macrophages in lesions, which prompted us to examine its effects on macrophages in more detail. We examined the effects of A387-TSP-4 and P387-TSP-4 on mouse macrophages in cell culture and in vivo in the model of LPS-induced peritonitis. In tissues and in cell culture, TSP-4 expression was associated with inflammation: TSP-4 expression was upregulated in peritoneal tissues in LPS-induced peritonitis, and pro-inflammatory signals, INFγ, GM-CSF, and LPS, induced TSP-4 expression in macrophages in vivo and in cell culture. Deficiency in TSP-4 in macrophages from Thbs4 − /− mice reduced the expression of pro-inflammatory macrophage markers, suggesting that TSP-4 facilitates macrophage differentiation into a pro-inflammatory phenotype. Expression of TSP-4, especially more active P387-TSP-4, was associated with higher cellular apoptosis. Cultured macrophages displayed increased adhesion to TSP-4 and reduced migration in presence of TSP-4, and these responses were further increased with P387 variant. We concluded that TSP-4 expression in macrophages increases their accumulation in tissues during the acute inflammatory process and supports macrophage differentiation into a pro-inflammatory phenotype. In a model of acute inflammation, TSP-4 supports pro-inflammatory macrophage apoptosis, a response that is closely related to their pro-inflammatory activity and release of pro-inflammatory signals. P387-TSP-4 was found to be the more active form of TSP-4 in all examined functions.