Abstract
Given the importance of high-mobility group box 1 (HMGB1) and 5-lipoxygenase (5-LO) signaling in vascular inflammation, we investigated the role of leukotriene signaling in monocytes on monocyte-to-macrophage differentiation (MMD) induced by HMGB1, and on vascular inflammation and subsequent intimal hyperplasia in a mouse model of wire-injured femoral artery. In cultured primary bone marrow-derived cells (BMDCs) stimulated with HMGB1, the number of cells with macrophage-like morphology was markedly increased in association with an increased expression of CD11b/Mac-1, which were attenuated in cells pre-treated with Zileuton, a 5-LO inhibitor as well as in 5-LO-deficient BMDCs. Of various leukotriene receptor inhibitors examined, which included leukotriene B4 receptors (BLTRs) and cysteinyl leukotriene receptors (cysLTRs), the BLTR1 inhibitor (U75302) exclusively suppressed MMD induction by HMGB1. The importance of BLTR1 in HMGB1-induced MMD was also observed in BMDCs isolated from BLTR1-deficient mice and BMDCs transfected with BLTR1 siRNA. Although leukotriene B4 (LTB4) had minimal direct effects on MMD in control and 5-LO-deficient BMDCs, MMD attenuation by HMGB1 in 5-LO-deficient BMDCs was significantly reversed by exogenous LTB4, but not in BLTR1-deficient BMDCs, suggesting that LTB4/BLTR1-mediated priming of monocytes is a prerequisite of HMGB1-induced MMD. In vivo, both macrophage infiltration and intimal hyperplasia in our wire-injured femoral artery were markedly attenuated in BLTR1-deficient mice as compared with wild-type controls, but these effects were reversed in BLTR1-deficient mice transplanted with monocytes from control mice. These results suggest that BLTR1 in monocytes is a pivotal player in MMD with subsequent macrophage infiltration into neointima, leading to vascular remodeling after vascular injury.
Highlights
Vascular endoluminal interventional procedures injure vascular walls, and result in the release endogenous damageassociated molecular patterns (DAMPs) [1, 2]
We investigated the importance of leukotriene signaling in monocytes on monocyte-to-macrophage differentiation and vascular inflammation and resultant intimal hyperplasia in a mouse model of wire-injured femoral artery
In cultured primary Bone marrow derived cell (BMDC), genetic or pharmacological inhibition of the 5-lipoxygenase pathway in monocytes attenuated monocyte-to-macrophage differentiation (MMD) induced by high-mobility group box 1 (HMGB1), an endogenous damageassociated molecular patterns
Summary
Vascular endoluminal interventional procedures injure vascular walls, and result in the release endogenous damageassociated molecular patterns (DAMPs) [1, 2]. Of the various DAMP proteins, high mobility group box 1 protein (HMGB1) has emerged as an important regulator of inflammatory responses resulting from tissue injury [3,4,5], and been implicated as an active player in vascular inflammation with resultant intimal hyperplasia after arterial injury [6]. Monocyte recruitment to injured tissues, their subsequent transformation into macrophages, and the overproduction of inflammatory cytokines are major steps in the process of vascular inflammation [8, 9]. These sequential events stimulate vascular smooth muscle cell (VSMC) proliferation and extracellular matrix deposition in neointima, which result in intimal hyperplasia and vascular occlusion [10]. Several key proteins involved in the leukotriene cascades, such as, 5-lipoxygenase (5-LO) and arachidonate 5-lipoxygenase activating protein (FLAP), and leukotriene (LT) receptors are highly expressed in human atherosclerotic plaque [11,12,13], which suggests their potential involvements in vascular inflammation
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