Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice.
Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice.
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DOI：
10.1371/journal.pone.0009539
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发表时间：
2010-03-04
期刊：
影响因子：
3.7
通讯作者：
Roy S
中科院分区：
文献类型：
--
作者：
Khanna S;Biswas S;Shang Y;Collard E;Azad A;Kauh C;Bhasker V;Gordillo GM;Sen CK;Roy S
慢性炎症是糖尿病皮肤伤口的一个特征。我们试图描述糖尿病皮肤伤口炎症消退障碍的新机制。在伤口部位，有效的死细胞清除（efferocytosis）是及时解决炎症和成功愈合的先决条件。从糖尿病小鼠伤口中分离的巨噬细胞显示出明显的红细胞功能障碍。受损的efferocytosis与伤口组织中凋亡细胞的负担显著增加以及促炎细胞因子的高表达和抗炎细胞因子的低表达有关。在糖尿病和非糖尿病患者的伤口组织中，与小鼠伤口部位凋亡细胞负荷相关的观察结果得到了验证。强迫Fas配体驱动的伤口部位凋亡细胞负荷的升高增强了促炎和减弱抗炎细胞因子反应。此外，成功的efferocytosis将伤口巨噬细胞从促炎模式切换到抗炎模式。综上所述，本研究提供了第一个证据，证明糖尿病伤口遭受功能失调的巨噬细胞efferocytosis，导致伤口部位凋亡细胞负荷增加。这种负担反过来又延长了炎症期并使伤口愈合复杂化。
Chronic inflammation is a characteristic feature of diabetic cutaneous wounds. We sought to delineate novel mechanisms involved in the impairment of resolution of inflammation in diabetic cutaneous wounds. At the wound-site, efficient dead cell clearance (efferocytosis) is a pre-requisite for the timely resolution of inflammation and successful healing. Macrophages isolated from wounds of diabetic mice showed significant impairment in efferocytosis. Impaired efferocytosis was associated with significantly higher burden of apoptotic cells in wound tissue as well as higher expression of pro-inflammatory and lower expression of anti-inflammatory cytokines. Observations related to apoptotic cell load at the wound site in mice were validated in the wound tissue of diabetic and non-diabetic patients. Forced Fas ligand driven elevation of apoptotic cell burden at the wound site augmented pro-inflammatory and attenuated anti-inflammatory cytokine response. Furthermore, successful efferocytosis switched wound macrophages from pro-inflammatory to an anti-inflammatory mode. Taken together, this study presents first evidence demonstrating that diabetic wounds suffer from dysfunctional macrophage efferocytosis resulting in increased apoptotic cell burden at the wound site. This burden, in turn, prolongs the inflammatory phase and complicates wound healing.
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