Higher expression of Bax in regulatory T cells increases vascular inflammation

Abstract

This study is to examine our hypothesis that CD4+CD25 high Foxp3+ regulatory T cells (Tregs) have an interleukin-2 (IL-2) withdrawal-triggered apoptosis pathway, and modulation of Treg apoptosis pathway affects development of vascular inflammation. We found that pro-apoptotic protein Bax upregulation in Tregs is induced by IL-2 withdrawal. Treg apoptosis induced by IL-2 withdrawal is inhibited by a Bax inhibitor, suggesting that highly expressed Bax is functional. To define the role of upregulated Bax in Treg apoptosis, we established a Tregs-specific Bax transgenic mouse model. Enforced expression of Bax in Tregs promotes Treg apoptosis triggered by IL-2 withdrawal and other apoptosis stimuli, suggesting pro-apoptotic role of highly expressed Bax in wild-type Tregs. Finally, higher expression of Bax in Tregs decreases the striking threshold of vascular inflammation due to the failure of suppression of inflammatory cells resulting from Treg apoptosis. These results have demonstrated the proof of principle that the modulation of Tregs apoptosis/survival could be used as a new therapeutic approach for inflammatory cardiovascular diseases. KeywordsRegulatory T Cells; Apoptosis; Bax; Inflammation; Vasculitis INTRODUCTIONCD4+CD25 high Foxp3+ regulatory T cells (Tregs), comprising 5-10% of CD4+ T cells(1), exhibit potent immunosuppressive functions(2) in the regulation of autoimmunity and inflammatory atherosclerosis (3,4). Naturally occurring Treg cells (thymus-generated, nTreg cells), as an independent subset, are engaged in the maintenance of immunological selftolerance and inhibition of various immune responses (5) and inflammatory atherogenesis. nTregs (Tregs in the rest of paper) appear to have specific apoptosis pathways since Treg cells have higher susceptibility to apoptosis (6), especially to IL-2 withdrawal-induced apoptosis. Tregs are poor IL-2 producers(7), implying that insufficient paracrine IL-2 supply to Tregs in pathological conditions could be responsible for higher susceptibility of Tregs to apoptosis. However, intracellular regulation of IL-2 insufficiency-triggered Treg apoptosis remains poorly defined. The Bcl-2/Bcl-xL protein family members play a central role in the Send correspondence to: Xiao-Feng Yang, Department of Pharmacology, Temple University School of Medicine, 3420 North Broad Street, MRB, Rm. 325, Philadelphia, PA 19140, Tel: 215-707-5985, Fax: 215-707-7068 MATERIALS AND METHODS Construction of CD25+ T cell-targeting mouse IL-2Rα promoter-Bax transgenic miceMouse IL-2 receptor α chain (CD25) promoter −2539 to +93 (GenBank Accession Number: M16398) vector pmIL2Rα-CAT1 (6.9 kb) was generously provided by P. Reichenbach and M. Nabholz(14). The construction of the CD25+ T cell targeting vector pCD25-Tg was described previously (10). The transgenic vector pCD25-Bax-Tg was verified by DNA sequencing by SeqWright Company (Houston, TX). The 3.818 kb transgenic DNA fragment "Nru I-CD25 promoter-C-Myc-Bax-Sex AI" was prepared by digesting the pCD25-Bax-Tg vector with three restrict...

Stat3-dependent acute Rantes production in vascular smooth muscle cells modulates inflammation following arterial injury in mice

“…Initial evidence arose from broad knockdown models, including clodronate-induced macrophage depletion (39), anti-CD11b antibody administration (8), and Rag -/-mice with absence of B and T lymphocytes (1), in which depletion of macrophages/lymphocytes/neutrophils led to reduced neointimal formation. While certain regulatory subtypes retard vascular inflammation (6,7), the paradigm that macrophages and T cells generally enhance inflammation and neointimal formation has been reinforced by genetic deletion of key surface antigens such as P-selectin glycoprotein ligand-1 (12), CCR2 (10, 11), CXCR3 (5), and CX3CR1 (13) or the inhibition of specific chemokines including monocyte chemotactic protein-1 (Mcp-1) (11), stromal cell-derived factor-1 (Sdf-1) (2), and Rantes (14). Rantes promoter activity (19,36) and transcription (40) may be stimulated by Tnf-α and mediated by NF-κB in various non-VSMC populations.…”

“…While certain regulatory subtypes differ in their responses (6,7), macrophage and T cell recruitment typically leads to enhanced inflammation and neointimal formation as well as reduced luminal patency (1,2,5,(8)(9)(10)(11). A complex network of cytokines, chemokines, and their receptors is known to regulate recruitment of these cells (2,5,(10)(11)(12)(13)(14).…”

Phytoestrogen calycosin-7-O-β-D-glucopyranoside ameliorates advanced glycation end products-induced HUVEC damage

“…Furthermore, chronic inflammation can modulate Bcl-2 family proteins expression and induce cell apoptosis [Xiong et al, 2008], thus CG may indirectly downregulate Bax and Bad while upregulate Bcl-2 expression and inhibit HUVEC apoptosis via ameliorating cell inflammation. On the other hand, there was report indicating that phytoestrogen might decrease Bcl-2 while increase Bad and Bad expression and inhibit tumor cell proliferation [Ferenc et al, 2010].…”

Uremic toxins are conditional danger- or homeostasis-associated molecular patterns

“…Finally, we wanted to examine a new hypothesis that CD4+Foxp3+ regulatory T cells (Tregs), one of the well-characterized immune tolerance cells, since we and others reported that Tregs play a critical role in suppressing vascular inflammation (13– 15); and that Tregs are weakened and expanded poorly in CKD patients in hemodialysis (55). As shown in Table 14, in Tregs versus T effector cells, 11 UT genes were upregulated; and 21 UT genes were downregulated.…”

“…We and others have previously shown that hyperlipidemia, along with other CVD stressors, such as hyperglycemia, hyperhomocysteinemia, and chronic kidney disease, promote atherosclerosis and vascular inflammation via several mechanisms (2–7). These mechanisms include endothelial cell (EC) activation and injury (2,8–10); mitochondrial reactive oxygen species (3); monocyte recruitment and differentiation (11,12); decreased regulatory T cells (13–15); impaired vascular repair ability of bone marrow–derived progenitor cells (16, 17); and downregulated histone modification enzymes (18). …”