Differential Activation of Inflammatory Pathways in Testicular Macrophages Provides a Rationale for Their Subdued Inflammatory Capacity
Differential Activation of Inflammatory Pathways in Testicular Macrophages Provides a Rationale for Their Subdued Inflammatory Capacity
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DOI：
10.4049/jimmunol.1401132
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发表时间：
2015-06-01
影响因子：
4.4
通讯作者：
Meinhardt, Andreas
中科院分区：
文献类型：
--
作者：
Bhushan, Sudhanshu;Tchatalbachev, Svetlin;Meinhardt, Andreas
生精细胞表达细胞特异性分子，具有被免疫系统视为“外来物”的潜力。由于它们在青春期出现和出生前后淋巴细胞库编辑之间的时间差，需要免疫系统的局部适应性创造免疫豁免来保护免受自动攻击。睾丸巨噬细胞（TM）在维持睾丸免疫豁免中起重要作用，与其他巨噬细胞相比，其促炎能力降低。然而，这种巨噬细胞表型的分子机制仍然难以捉摸。我们证明，TM有一个较低的组成型表达TLR通路特异性基因相比，腹腔巨噬细胞。此外，在用LPS刺激的TM中，NF-κ B信号传导途径由于缺乏I κ B α泛素化而被阻断，因此降解。相反，用LPS或聚肌胞苷酸（polyinosinic-polycytidylic acid）刺激TM诱导MAPK、AP-1和CREB信号通路，这导致促炎细胞因子如TNF-α的产生，尽管其水平比腹膜巨噬细胞低得多。用MAPK p38和ERK 1/2抑制剂预处理TM可抑制AP-1和CREB信号通路的激活，并减弱LPS诱导的TNF-α和IL-10分泌。TM中通过LPS刺激的高水平IL-10产生和STAT 3活化表明调节性巨噬细胞表型。我们的研究结果表明，TM通过抑制NF-κ B信号转导，通过I κ B α泛素化和TLR级联基因表达的普遍减少，维持睾丸免疫赦免。然而，TM确实通过AP-1和CREB信号通路保持了一定的先天免疫反应能力。
Spermatogenic cells express cell-specific molecules with the potential to be seen as "foreign" by the immune system. Owing to the time difference between their appearance in puberty and the editing of the lymphocyte repertoire around birth, local adaptations of the immune system coined immune privilege are required to confer protection from autoattack. Testicular macrophages (TM) play an important role in maintaining testicular immune privilege and display reduced proinflammatory capacity compared with other macrophages. However, the molecular mechanism underlying this macrophage phenotype remained elusive. We demonstrate that TM have a lower constitutive expression of TLR pathway-specific genes compared with peritoneal macrophages. Moreover, in TM stimulated with LPS, the NF-kappa B signaling pathway is blocked due to lack of I kappa B alpha ubiquitination and, hence, degradation. Instead, challenge of TM with LPS or polyinosinic-polycytidylic acid induces MAPK, AP-1, and CREB signaling pathways, which leads to production of proinflammatory cytokines such as TNF-alpha, although at much lower levels than in peritoneal macrophages. Pretreatment of TM with inhibitors for MAPKs p38 and ERK1/2 suppresses activation of AP-1 and CREB signaling pathways and attenuates LPS-induced TNF-alpha and IL-10 secretion. High levels of IL-10 production and activation of STAT3 by LPS stimulation in TM indicate a regulatory macrophage phenotype. Our results suggest that TM maintain testicular immune privilege by inhibiting NF-kappa B signaling through impairment of I kappa B alpha ubiquitination and a general reduction of TLR cascade gene expression. However, TM do maintain some capacity for innate immune responses through AP-1 and CREB signaling pathways.