Novel Role of the CXC Chemokine Receptor 3 in Inflammatory Response to Arterial Injury

Abstract

Abstract-Atherosclerosis, restenosis, and posttransplant graft atherosclerosis are characterized by endothelial damage, infiltration of inflammatory cells, and proliferation of smooth muscle cells. The CXCR3-activating chemokines interferon-␥ inducible protein 10 (IP10) and MIG (monokine induced by interferon-␥) have been implicated in vascular repair and remodeling. The underlying molecular mechanisms, however, remain elusive. Here, we show that wire-mediated arterial injury induced local and systemic expression of IP10 and MIG, resulting in enhanced recruitment of CXCR3 ϩ leukocytes and hematopoietic progenitor cells. This was accompanied by profound activation of mammalian target of rapamycin complex (mTORC)1, increased reactive oxygen species production, apoptosis, and intimal hyperplasia. Genetic and pharmacological inactivation of CXCR3 signaling not only suppressed recruitment of inflammatory cells but also abolished mTORC1 activation, reduced reactive oxygen species generation, and blocked apoptosis of vascular cells, resulting in significant reduction of intimal hyperplasia in vivo. In vitro, stimulation of T cells with IP10 directly activated mTORC1 and induced generation of reactive oxygen species and apoptosis in an mTORC1-dependent manner. These results strongly indicate that CXCR3-dependent activation of mTORC1 directly links stimulation of the Th1 immune system with the proliferative response of intimal cells in vascular remodeling. T he impact of inflammation in atherosclerosis, the most important cause of morbidity in the Western world, has been well known for a long time. 1 Injury of the endothelium by proatherogenic factors such as free radicals, hypertension, and diabetes mellitus or by mechanical stress during percutaneous coronary intervention induces an early inflammatory reaction, resulting in infiltration of T cells and monocytes into the injured vessel. [1][2][3] This defined recruitment of inflammatory cells is essential for development of atherosclerosis and vascular remodeling in response to arterial injury. 4 Infiltration of inflammatory cells is accurately regulated by various members of the CC as well as CXC family of chemokines and their corresponding receptors. 4 The essential role of chemokines for vascular remodeling is highlighted by recent animal data suggesting that blocking chemokine/chemokine receptor interactions interferes with vascular remodeling. 5 Among other chemokine receptors, activation of the CXC chemokine receptor (CXCR)3 by interferon (IFN)-␥ inducible protein 10 (IP10) and MIG (monokine induced by IFN-␥) is critically involved in the recruitment of CXCR3-positive T helper type 1 lymphocytes (Th1 cells) in atheromas. 6 Likewise, blockade or depletion of CXCR3 severely attenuates recruitment of Th1 cells to the sites of inflammation and significantly reduces early steps of atherogenesis. 7-9 However, to date, the role of CXCR3 activation in the vascular response to arterial injury has not been investigated.The molecular mechanisms linking the Th1 immune sy...

Intimal hyperplasia: slow but deadly

“…The VEC is a multifaceted regulator of vascular function including vascular tone, 12 the coagulation cascade, 13 and angiogenesis, 14 and also possesses macrophage functional traits, including recruitment of inflammatory cells through cytokine and chemokine secretion, human leukocyte antigen (HLA) class I and II molecule expression, and antigen presentation. 15,16 Most importantly, any VEC injury that causes VEC dysfunction increases the probability for IH formation. 17 As an example, ischemicreperfusion-injury (IRI) during organ preservation has been associated with VEC injury and IH [18], 18 including The sections are from mouse carotid arteries following the intimal hyperplasia method described by Kumar et al 95 The left hand sections were stained with Verhoeff stain for elastin (dark brown/black) and the right hand panels were stained with picroSirus red and visualized under polarized light to reveal collagen fibers (yellow/orange).…”

Pentoxifylline Reduces Tumor Necrosis Factor-α and HIV-Induced Vascular Endothelial Activation

“…25 The chemokine IP-10 has been previously described to promote two key processes involved in atherosclerosis, namely Th1 immune system activation and endothelial apoptosis. 26,27 In the present study, we tried to determine whether we could identify the cellular mechanisms underlying the beneficial effects observed in our clinical PTX treatment trial. Thus, we investigated the role of the HIV-1 proteins gp120 and Tat in combination with proinflammatory cytokines in the presence and absence of PTX in both primary human lung microvascular endothelial cells (HLMVECs) and human coronary arterial endothelial cells (HCAECs).…”

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

“…An additional key component of this process is the recruitment of macrophages and T cells (1,2,5). 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).…”

“…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).…”