Alteration of Lysosome Fusion and Low-grade Inflammation Mediated by Super-low-dose Endotoxin
Alteration of Lysosome Fusion and Low-grade Inflammation Mediated by Super-low-dose Endotoxin
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DOI：
10.1074/jbc.m114.611442
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发表时间：
2015-03-06
影响因子：
4.8
通讯作者：
Li, Liwu
中科院分区：
文献类型：
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作者：
Baker, Bianca;Geng, Shuo;Li, Liwu
亚临床超低剂量内毒素I，PS是慢性疾病发病和进展过程中建立低度炎症的危险因素。然而，其潜在机制尚不清楚。在细胞水平，溶酶体与内体或自噬体融合的破坏可能有助于增强低度炎症。在这项研究中，我们发现亚临床超低剂量内毒素LPS可以有效地抑制原代巨噬细胞内体酸化和溶酶体与内体或自噬体融合的过程。超低剂量LPS诱导VPS 34的抑制性磷酸化，从而导致内体-溶酶体融合的破坏。这种作用可能依赖于超低剂量LPS对巨噬细胞内Tollip的清除和迁移。与此观点一致，Tollip缺陷型巨噬细胞具有组成性升高的VPS 34抑制性磷酸化水平和内体-溶酶体融合的组成性破坏。通过采用皮肤切除伤口愈合模型，我们观察到Tollip缺陷小鼠的细胞应激水平显著升高，伤口修复减少。这项研究揭示了一种新的机制，负责调节内体-溶酶体融合和低度炎症的先天性巨噬细胞。
Subclinical super-low-dose endotoxin I,PS is a risk factor for the establishment of low-grade inflammation during the pathogenesis and progression of chronic diseases. However, the underlying mechanisms are not well understood. At the cellular level, a disruption of lysosome fusion with endosomes or autophagosomes may contribute to the potentiation of low-grade inflammation. In this study, we identified that subclinical super-low-dose endotoxin LPS can potently inhibit the process of endosome acidification and lysosome fusion with endosomes or autophagosomes in primary macrophages. Super-low-dose LPS induced the inhibitory phosphorylation of VPS34, thus leading to the disruption of endosome-lysosome fusion. This effect may depend upon the clearance and relocation of Tollip in macrophages by super-low-dose LPS. Consistent with this notion, Tollip-deficient macrophages had constitutively elevated levels of VPS34 inhibitory phosphorylation and constitutive disruption of endosome-lysosome fusion. By employing a skin excision wound-healing model, we observed that Tollip-deficient mice had significantly elevated levels of cell stress and reduced wound repair. This study reveals a novel mechanism responsible for the modulation of endosome-lysosome fusion and low-grade inflammation in innate macrophages.