Abstract
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.
Highlights
Thrombospondin-4 (TSP-4) is a matricellular protein, one of the five members of thrombospondin family[1,2]
We examined the effects of pro-inflammatory (LPS, IFNγ, and GM-CSF) and anti-inflammatory stimuli (MCSF and IL-4) on the levels of TSP-4 protein and mRNA in RAW 264.7 cells (Fig. 2a–c) and in Bone-marrow-derived macrophages (BMDM) (Fig. 2d–f)
Tissue remodeling is associated with inflammation, and we reported that TSP-4 deficiency results in reduced inflammation in atherosclerotic lesions in ApoE−/− mice: the number of macrophages in the atherosclerotic lesion and the local vascular inflammation were reduced in Thbs4−/−/ApoE−/− mice[14]
Summary
Thrombospondin-4 (TSP-4) is a matricellular protein, one of the five members of thrombospondin family[1,2]. Rahman et al Cell Death and Disease (2020)11:53 effects depend on its intracellular interactions: its binding to the ER lumenal domain of activating transcription factor 6α (Atf6α) protects cardiomyocytes from injury caused by ER stress responses[7] This protein exerts its effect in multiple complementary ways: by initiating intracellular signaling and transiting through secretory pathways[38], as well as by binding to its extracellular ligands and receptors upon secretion[5,6,14,24,30,33,37,39,40,41,42,43,44,45,46,47,48].
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