Cross-tolerization between Nod1 and Nod2 signaling results in reduced refractoriness to bacterial infection in Nod2-deficient macrophages
Cross-tolerization between Nod1 and Nod2 signaling results in reduced refractoriness to bacterial infection in Nod2-deficient macrophages
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DOI：
10.4049/jimmunol.181.6.4340
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发表时间：
2008-09-15
影响因子：
4.4
通讯作者：
Nunez, Gabriel
中科院分区：
文献类型：
--
作者：
Kim, Yun-Gi;Park, Jong-Hwan;Nunez, Gabriel
Nod2 是一种细胞内先天免疫受体，在宿主防御和炎症性疾病易感性中发挥作用。我们在这项研究中表明，通过暴露于 LPS 和胞壁酰二肽 (MDP)，巨噬细胞对 TLR4 和 Nod2 信号传导产生抵抗，在对致病性单核细胞增生李斯特氏菌和假结核耶尔森氏菌以及包括大肠杆菌和拟杆菌在内的共生细菌的反应中，TNF-α 和 IL-6 的产生受损。 脆弱。令人惊讶的是，Nod2 缺乏与对致病菌和共生菌的耐受性受损有关。从机制上讲，Nod2 缺失巨噬细胞的耐受性降低是通过 Nod1 识别细菌介导的，因为它在 Nod1 和 Nod2 缺陷的巨噬细胞中被消除。一致地，对 LPS 和 MDP 耐受的 Nod2 缺失巨噬细胞表现出 TNF-a 和 IL-6 的产生增强，以及对二肽 KF1B（Nod1 激动剂）的反应增加 NF-κ B 和 MAPK 激活。此外，当突变型巨噬细胞也对Nod1配体产生耐受性时，Nod2缺陷型巨噬细胞对细菌的耐受性降低就被消除了。最后，MDP 刺激不仅诱导 MDP 耐受，而且诱导 iE-DAP 刺激耐受，这提供了一种机制来解释感染细菌的 Nod2 缺陷型巨噬细胞的耐受性降低。这些结果表明，Nod1 和 Nod2 之间的交叉耐受导致预先暴露于微生物配体的 Nod2 缺陷巨噬细胞中对病原菌和共生菌的识别增加。
Nod2 is an intracellular innate immune receptor that plays a role in host defense and susceptibility to inflammatory disease. We show in this study that macrophages rendered refractory to TLR4 and Nod2 signaling by exposure to LPS and muramyl dipeptide (MDP) exhibit impaired TNF-alpha and IL-6 production in response to pathogenic Listeria monocytogenes and Yersinia pseudotuberculosis as well as commensal bacteria including Escherichia coli and Bacteroides fragilis. Surprisingly, Nod2 deficiency was associated with impaired tolerization in response to pathogenic and commensal bacteria. Mechanistically, reduced tolerization of Nod2-null macrophages was mediated by recognition of bacteria through Nod1 because it was abolished in macrophages deficient in Nod1 and Nod2. Consistently, Nod2-null macrophages tolerant to LPS and MDP showed enhanced production of TNF-a and IL-6 as well as increased NF-kappa B and MAPK activation in response to the dipeptide KF1B, the Nod1 agonist. Furthermore, reduced tolerization of Nod2-deficient macrophages in response to bacteria was abolished when mutant macrophages were also rendered tolerant to the Nod1 ligand. Finally, MDP stimulation induced refractoriness not only to MDP, but also to iE-DAP stimulation, providing a mechanism to explain the reduced tolerization of Nod2-deficient macrophages infected with bacteria. These results demonstrate that cross-tolerization between Nod1 and Nod2 leads to increase recognition of both pathogenic and commensal bacteria in Nod2-deficient macrophages pre-exposed to microbial ligands.