Specialized regulatory T cells control venous blood clot resolution through SPARC

Abstract

The cells and mechanisms involved in blood clot resorption are only partially known. We show that regulatory T (Treg) cells accumulate in venous blood clots and regulate thrombolysis by controlling the recruitment, differentiation and matrix metalloproteinase (MMP) activity of monocytes. We describe a clot Treg population that forms the matricellular acid- and cysteine-rich protein (SPARC), show that SPARC enhances monocyte MMP activity and that SPARC+ Treg are crucial for blood clot resorption. By comparing different treatment times, we define a therapeutic window of Treg expansion that accelerates clot resorption.

CSF and serum inflammatory response and association with outcomes in spontaneous intracerebral hemorrhage with intraventricular extension: an analysis of the CLEAR-III Trial

“…We found an association between CSF lymphocyte count and percent IVH clearance, which may be due to crosstalk between lymphocytes and the coagulation system. In addition to crosstalk with platelets [ 34 ], regulatory T cells producing SPARC (secreted protein acidic and rich in cysteine) are crucial for blood clot resorption [ 35 ] and may contribute to reduction of hemorrhage volume.…”

SPARCing the clot

“…In this issue of Blood, Khan et al 1 reported that high-dose chemotherapy and autologous hematopoietic cell transplantation (auto-HCT) are associated with decreased fecal microbiota diversity and that patients with a greater degree of microbiome damage (below-median fecal intestinal diversity) at neutrophil engraftment had worse progression-free survival than those with less microbiome damage.…”

“…Here, the authors have characterized these thrombus Tregs and elucidate their role in thrombus resolution. 1 To induce a thrombus, the authors used a mouse model of partial flow reduction in the inferior vena cava. By isolating immune cells at different time points after the partial occlusion, they showed that Tregs accumulate in the thrombus over time.…”

“…[6][7][8] Detailed investigation into the role of SPARC 1 Tregs showed that SPARC does not mitigate Treg-mediated regulation of the adaptive immune system. SPARC 1 Tregs rather mediate innate immune cell functions and boost MMP production by monocytes, thereby facilitating clot resolution (see figure). The data that Tregs produce SPARC when stimulated with interleukin-18 (IL-18), IL-33, and transforming growth factor-b (TGF-b), without T-cell receptor stimulation, strengthen the hypothesis that SPARC are tissue induced, especially because these cytokines are all associated with the vasculature, where they are produced by the endothelial cells.…”

Advances in understanding the interplay between adaptive and innate immunity in experimental venous thrombus resolution

“…Shahneh et al, 20 in a series of sophisticated experiments, elaborate on another previously understudied adaptive immune cell in venous thrombus resolution: the regulatory T cell (Treg). Tregs, identified as CD4+, CD25+ cells with selective expression of Foxp3, function as immunomodulators, essential for preventing exuberant inflammation.…”