TRAIL-R1 Is a Negative Regulator of Pro-Inflammatory Responses and Modulates Long-Term Sequelae Resulting from Chlamydia trachomatis Infections in Humans

The immune system eliminates Chlamydia trachomatis infection through inflammation. However, uncontrolled inflammation can enhance pathology. In mice, TNF-related apoptosis-inducing ligand receptor (TRAIL-R), known for its effects on apoptosis, also regulates inflammation. In humans, the four homologues of TRAIL-R had never been investigated for effects on inflammation. Here, we examined whether TRAIL-R regulates inflammation during chlamydial infection. We examined TRAIL-R1 single nucleotide polymorphisms (SNPs) in an Ecuadorian cohort with and without C. trachomatis infections. There was a highly significant association for the TRAIL+626 homozygous mutant GG for infection vs no infection in this population. To confirm the results observed in the human population, primary lung fibroblasts and bone marrow-derived macrophages (BMDMs) were isolated from wildtype (WT) and TRAIL-R-deficient mice, and TRAIL-R1 levels in human cervical epithelial cells were depleted by RNA interference. Infection of BMDMs and primary lung fibroblasts with C. trachomatis strain L2, or the murine pathogen C. muridarum, led to higher levels of MIP2 mRNA expression or IL-1β secretion from TRAIL-R-deficient cells than WT cells. Similarly, depletion of TRAIL-R1 expression in human epithelial cells resulted in a higher level of IL-8 mRNA expression and protein secretion during C. trachomatis infection. We conclude that human TRAIL-R1 SNPs and murine TRAIL-R modulate the innate immune response against chlamydial infection. This is the first evidence that human TRAIL-R1 is a negative regulator of inflammation and plays a role in modulating Chlamydia pathogenesis.免疫系统可通过炎症反应清除沙眼衣原体（Chlamydia trachomatis）感染，但失控的炎症反应会加重病理损伤。在小鼠模型中，以往被证实参与凋亡调控的肿瘤坏死因子相关凋亡诱导配体受体（TRAIL-R），同时也可调控炎症反应。而在人类中，TRAIL-R的四种同源蛋白是否参与炎症调控此前尚未见相关研究报道。本研究旨在探究TRAIL-R在衣原体感染过程中对炎症反应的调控作用。我们针对厄瓜多尔沙眼衣原体感染阳性及阴性队列人群，开展了TRAIL-R1单核苷酸多态性（SNPs）分析。结果显示，该人群中TRAIL+626位点纯合突变型GG与沙眼衣原体感染状态存在极显著相关性。为验证人群研究所得结果，我们分别从野生型（WT）及TRAIL-R基因敲除小鼠体内分离原代肺成纤维细胞与骨髓来源巨噬细胞（BMDMs），并通过RNA干扰（RNA interference）技术敲低人宫颈上皮细胞中的TRAIL-R1表达水平。用沙眼衣原体L2毒株或鼠衣原体（C. muridarum）感染上述BMDMs与原代肺成纤维细胞后，TRAIL-R基因敲除细胞的巨噬细胞炎性蛋白2（MIP2）mRNA表达水平及白细胞介素1β（IL-1β）分泌量均显著高于野生型细胞。同样，敲低人上皮细胞的TRAIL-R1表达后，沙眼衣原体感染诱导的白细胞介素8（IL-8）mRNA表达水平与蛋白分泌量均显著升高。综上，人类TRAIL-R1基因多态性与小鼠TRAIL-R均可调控抗衣原体感染的固有免疫应答。本研究首次证实，人类TRAIL-R1是炎症反应的负调控因子，并在沙眼衣原体感染的发病机制中发挥调控作用。