Stimulation by toll-like receptors inhibits osteoclast differentiation
Stimulation by toll-like receptors inhibits osteoclast differentiation
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DOI：
10.4049/jimmunol.169.3.1516
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发表时间：
2002-08-01
影响因子：
4.4
通讯作者：
Choi, Y
中科院分区：
文献类型：
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作者：
Takami, M;Kim, N;Choi, Y
破骨细胞是能够吸收骨的细胞，源自单核细胞-巨噬细胞谱系的造血前体细胞。相同的前体细胞还可以产生巨噬细胞和树突细胞，这对于对各种病原体的适当免疫反应至关重要。对微生物病原体的免疫反应常常被触发，因为各种微生物成分通过刺激 Toll 样受体 (TLR) 诱导巨噬细胞或树突状细胞等免疫调节细胞的成熟和激活。由于破骨细胞与巨噬细胞来自相同的前体细胞，我们测试了 TLR 是否在破骨细胞分化过程中发挥作用。我们在此表明，从小鼠骨髓细胞制备的破骨细胞前体表达所有已知的小鼠 TLR（TLR1-TLR9）。此外，各种TLR配体（例如肽聚糖、聚（I：C）dsRNA、LPS和未甲基化DNA的CpG基序，分别作为TLR2、3、4和9的配体）诱导破骨细胞前体细胞中NF-κB激活并上调TNF-α产生。然而，出乎意料的是，这些微生物产物对破骨细胞前体的 TLR 刺激强烈抑制了它们分化为由 TNF 相关激活诱导的细胞因子诱导的多核成熟破骨细胞。相反，在破骨细胞刺激物 M-CSF 和 TNF 相关激活诱导的细胞因子存在下，TLR 刺激维持了破骨细胞前体的吞噬活性。综上所述，这些结果表明破骨细胞前体的 TLR 刺激抑制了微生物感染期间它们分化为非炎症性成熟破骨细胞。这一过程有利于免疫反应，对于防止微生物入侵骨骼的致病作用可能至关重要。
Osteoclasts, the cells capable of resorbing bone, are derived from hemopoietic precursor cells of monocyte-macrophage lineage. The same precursor cells can also give rise to macrophages and dendritic cells, which are essential for proper immune responses to various pathogens. Immune responses to microbial pathogens are often triggered because various microbial components induce the maturation and activation of immunoregulatory cells such as macrophages or dendritic cells by stimulating Toll-like receptors (TLRs). Since osteoclasts arise from the same precursors as macrophages, we tested whether TLRs play any role during osteoclast differentiation. We showed here that osteoclast precursors prepared from mouse bone marrow cells expressed all known murine TLRs (TLR1-TLR9). Moreover, various TLR ligands (e.g., peptidoglycan, poly(I:C) dsRNA, LPS, and CpG motif of unmethylated DNA, which act as ligands for TLR2, 3, 4, and 9, respectively) induced NF-kappaB activation and up-regulated TNF-alpha production in osteoclast precursor cells. Unexpectedly, however, TLR stimulation of osteoclast precursors by these microbial products strongly inhibited their differentiation into multinucleated, mature osteoclasts induced by TNF-related activation-induced cytokine. Rather, TLR stimulation maintained the phagocytic activity of osteoclast precursors in the presence of osteoclastogenic stimuli M-CSF and TNF-related activation-induced cytokine. Taken together, these results suggest that TLR stimulation of osteoclast precursors inhibits their differentiation into noninflammatory mature osteoclasts during microbial infection. This process favors immune responses and may be critical to prevent pathogenic effects of microbial invasion on bone.