The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages
The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages
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DOI：
10.1172/jci23755
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发表时间：
2005-08-01
影响因子：
15.9
通讯作者：
Gröne, HJ
中科院分区：
文献类型：
--
作者：
Schaefer, L;Babelova, A;Gröne, HJ
双糖链蛋白聚糖是一种富含亮氨酸的小蛋白聚糖，是一种普遍存在的 ECM 成分；然而，其生物学作用尚未详细阐明。在这里，我们发现双糖链蛋白聚糖在巨噬细胞中作为 TLR4 和 TLR2 的内源性配体发挥作用，介导先天免疫，导致 p38、ERK 和 NF-κ B 快速激活，从而刺激 TNF-α 和巨噬细胞炎症蛋白 2 (MIP-2) 的表达。一致地，双糖链蛋白聚糖的刺激作用在 TLR4 突变体 (TLR4-M)、TLR2(-/-) 和骨髓分化因子 88(-/-) (MyD88(-/-)) 巨噬细胞中显着降低，在 TLR2(-/-)/TLR4-M 巨噬细胞中完全消除。 Biglycan-mill 小鼠在 LPS 或酵母聚糖诱导的脓毒症中具有相当大的生存获益，因为循环 TNF-α 水平较低，肺部单核细胞浸润减少，从而减少了终末器官损伤。重要的是，当受到 LPS 诱导的促炎因子刺激时，巨噬细胞本身能够合成双糖链蛋白聚糖。因此，双聚糖从 ECM 或巨噬细胞释放后，可以通过 TLR4 和 TLR2 信号传导增强炎症，从而增强 TNF-α 和 MIP-2 的合成。据我们所知，我们的结果为基质成分双糖链蛋白聚糖作为信号分子和关键促炎因子的新作用提供了证据。这些发现可能与脓毒症治疗新策略的开发相关。
Biglycan, a small leucine-rich proteoglycan, is a ubiquitous ECM component; however, its biological role has not been elucidated in detail. Here we show that biglycan acts in macrophages as an endogenous ligand of TLR4 and TLR2, which mediate innate immunity, leading to rapid activation of p38, ERK, and NF-kappa B and thereby stimulating the expression of TNF-alpha and macrophage inflammatory protein-2 (MIP-2). In agreement, the stimulatory effects of biglycan are significantly reduced in TLR4-mutant (TLR4-M), TLR2(-/-), and myeloid differentiation factor 88(-/-) (MyD88(-/-)) macrophages and completely abolished in TLR2(-/-)/TLR4-M macrophages. Biglycan-mill mice have a considerable survival benefit in LPS- or zymosan-induced sepsis due to lower levels of circulating TNF-alpha and reduced infiltration of mononuclear cells in the lung, which cause less end-organ damage. Importantly, when stimulated by LPS-induced proinflammatory factors, macrophages themselves are able to synthesize biglycan. Thus, biglycan, upon release from the ECM or from macrophages, can boost inflammation by signaling through TLR4 and TLR2, thereby enhancing the synthesis of TNF-alpha and MIP-2. Our results provide evidence for what is, to our knowledge, a novel role of the matrix component biglycan as a signaling molecule and a crucial proinflammatory factor. These findings are potentially relevant for the development of new strategies in the treatment of sepsis.