Lymphotoxin β Receptor Activation on Macrophages Induces Cross-Tolerance to TLR4 and TLR9 Ligands
Lymphotoxin β Receptor Activation on Macrophages Induces Cross-Tolerance to TLR4 and TLR9 Ligands
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DOI：
10.4049/jimmunol.1103324
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发表时间：
2012-04-01
影响因子：
4.4
通讯作者：
Hehlgans, Thomas
中科院分区：
文献类型：
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作者：
Wimmer, Nadin;Huber, Barbara;Hehlgans, Thomas
我们以前的研究表明，光毒素β受体（LT β R）的激活控制和下调炎症反应。在这项研究中，我们报告了LT β R对原代小鼠巨噬细胞的激活导致诱导含有（TRIM）30 α的三重基序，该基序负调节TLR信号诱导的NF-κ B激活。LT β R激活导致TLR再刺激后促炎细胞因子和介质表达下调，表明LT β R信号传导参与TLR交叉耐受的诱导。使用TRIM 30 α特异性小干扰RNA的特异性敲低实验消除了TRIM 30 α和LT β R介导的TLR交叉耐受性的LT β R依赖性诱导。一致地，骨髓源性巨噬细胞上的LT β R活化在体外诱导对TLR 4和TLR 9配体的交叉耐受。此外，我们已经产生了细胞类型特异性的LT β R缺陷小鼠，其中巨噬细胞/中性粒细胞上的LT β R表达被消除（LT β R-flox/flox x LysM-Cre）。在来自这些小鼠的骨髓源性巨噬细胞中，LT β R诱导的对TLR 4和TLR 9配体的交叉耐受性受损。此外，巨噬细胞上LT β R表达的条件性消融（LT β R flox/flox 3 LysM-Cre）小鼠对LT β R诱导的体内TLR 4耐受性具有抗性。总的来说，我们的数据表明，T细胞衍生的光毒素α（1）β（2）激活巨噬细胞上的LT β R通过激活TRIM 30 α控制的反调节信号通路来控制促炎反应，以防止炎症反应加剧。免疫学杂志，2012，188：3426-3433。
Our previous studies indicated that lymphotoxin beta receptor (LT beta R) activation controls and downregulates inflammatory reactions. In this study, we report that LT beta R activation on primary mouse macrophages results in induction of tripartite motif containing (TRIM) 30 alpha, which negatively regulates NF-kappa B activation induced by TLR signaling. LT beta R activation results in a downregulation of proinflammatory cytokine and mediator expression upon TLR restimulation, demonstrating that LT beta R signaling is involved in the induction of TLR cross-tolerance. Specific knockdown experiments using TRIM30 alpha-specific small interfering RNA abolished the LT beta R-dependent induction of TRIM30 alpha and LT beta R-mediated TLR cross-tolerance. Concordantly, LT beta R activation on bone marrow-derived macrophages induced cross-tolerance to TLR4 and TLR9 ligands in vitro. Furthermore, we have generated cell type-specific LT beta R-deficient mice with ablation of LT beta R expression on macrophages/neutrophils (LT beta R-flox/flox x LysM-Cre). In bone marrow-derived macrophages derived from these mice LT beta R-induced cross-tolerance to TLR4 and TLR9 ligands was impaired. Additionally, mice with a conditional ablation of LT beta R expression on macrophages (LT beta R flox/flox 3 LysM-Cre) are resistant to LT beta R-induced TLR4 tolerance in vivo. Collectively, our data indicate that LT beta R activation on macrophages by T cell-derived lymphotoxin alpha(1)beta(2) controls proinflammatory responses by activation of a TRIM30 alpha-controlled, counterregulatory signaling pathway to protect against exacerbating inflammatory reactions. The Journal of Immunology, 2012, 188: 3426-3433.