Biology subjects

Muppala, S.

Publications and source records attributed to Muppala, S..

2 recordsLinked to original sources

bioRxiv2019

The P387 Thrombospondin-4 Variant Promotes Accumulation of Macrophages in Atherosclerotic Lesions

AimsThrombopspondin-4 (TSP4) is a pro-angiogenic protein that has been implicated in tissue remodeling and local vascular inflammation. TSP4 and, in particular, its SNP variant, P387 TSP4, have been associated with cardiovascular disease.\n\nMacrophages are central to initiation and resolution of inflammation and development of atherosclerotic lesions, but the effects of the P387 TSP4 on macrophages remain essentially unknown. We examined the effects of the P387 TSP4 variant on macrophages in cell culture and in vivo in a murine model of atherosclerosis. Further, the levels and distributions of the twoTSP4 variants were assessed in human atherosclerotic arteries.\n\nMethods and ResultsIn ApoE-/-/P387-TSP4 knock-in mice, atherosclerotic lesions accumulated more macrophages than lesions bearing A387 TSP4. The levels of inflammatory markers were increased in lesions of ApoE-/-/P387-TSP4 knock-in mice compared to ApoE-/- mice. Lesions in human arteries from individuals carrying the P387 variant had higher levels of TSP4 and higher macrophage accumulation. P387 TSP4 was more active in supporting adhesion of cultured human and mouse macrophages in experiments using recombinant TSP4 variants and in cells derived from P387-TSP4 knock-in mice.\n\nConclusionsTSP4 supports the adhesion of macrophages and their accumulation in atherosclerotic lesions. P387 TSP4 is more active in supporting these pro-inflammatory events in the vascular wall, which may contribute to the increased association of P387 TSP4 with cardiovascular disease.\n\nAbbreviationsBSA, bovine serum albumin; DMSO, dimethyl sulfoxide; ECM, extracellular matrix; Thbs4-/-, thrombospondin-4 gene knock-out; WT, wild type; P387-TSP4 KI, P387 TSP4 knock-in mice; OCT, Optimum Cutting Temperature; vWF, von Willebrand factor; -SMA, alpha-smooth muscle actin; Egr2, Early Growth Response 2; PBS, Phosphate Buffer saline; DMEM, Dulbeccos Modified Eagle Medium.

pathology↗

bioRxiv2019

Effect of Thrombospondin-4 on Pro-inflammatory Phenotype Differentiation and Apoptosis in Macrophages.

Thrombospondin-4 (TSP4) attracted a lot of attention recently as a result of new functions identified for this matricellular protein in cardiovascular, muscular, and nervous systems. We have previously reported that TSP4 promotes local vascular inflammation in mouse atherosclerosis model. A common variant of TSP4, P387-TSP4, was associated with increased cardiovascular disease risk in human population studies. In a mouse atherosclerosis model, TSP4 had profound effect on accumulation of macrophages in lesions, which prompted us to examine its effects on macrophages, more in detail in this report.\n\nWe 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, TSP4 expression was associated with inflammation: TSP4 expression was upregulated in peritoneal tissues in LPS-induced peritonitis, and pro-inflammatory signals, INF{gamma}, GM-CSF, and LPS, induced TSP4 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 pro-inflammatory phenotype. Expression of TSP4, especially more active P387-TSP4, was associated with higher cellular apoptosis. Cultured macrophages displayed increased adhesion to TSP4 and reduced migration in presence of TSP4, and these responses were further increased with P387 variant.\n\nWe concluded that TSP4 expression in tissue macrophages and in cultured 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, TSP4 supports pro-inflammatory macrophage apoptosis, a response that is closely related to their pro-inflammatory activity and release of pro-inflammatory signals. P387-TSP4 was found to be more active form of TSP4 in all examined functions.

cell biology↗