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首页> 外文期刊>Infection and immunity >Role of Toll Interleukin-1 Receptor (IL-1R) 8, a Negative Regulator of IL-1R/Toll-Like Receptor Signaling, in Resistance to Acute Pseudomonas aeruginosa Lung Infection
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Role of Toll Interleukin-1 Receptor (IL-1R) 8, a Negative Regulator of IL-1R/Toll-Like Receptor Signaling, in Resistance to Acute Pseudomonas aeruginosa Lung Infection

机译：IL-1R / Toll样受体信号的负调节剂Toll白介素1受体（IL-1R）8在对急性铜绿假单胞菌肺部感染的抵抗中的作用

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Toll interleukin-1 receptor (IL-1R) 8 (TIR8), also known as single Ig IL-1 receptor (IL-R)-related molecule, or SIGIRR, is a member of the IL-1R-like family, primarily expressed by epithelial cells. Current evidence suggests that TIR8 plays a nonredundant role as a negative regulator in vivo under different inflammatory conditions that are dependent on IL-R and Toll-like receptor (TLR) activation. In the present study, we examined the role of TIR8 in innate resistance to acute lung infections caused by Pseudomonas aeruginosa, a Gram-negative pathogen responsible for life-threatening infections in immunocompromised individuals and cystic fibrosis patients. We show that Tir8 deficiency in mice was associated with increased susceptibility to acute P. aeruginosa infection, in terms of mortality and bacterial load, and to exacerbated local and systemic production of proinflammatory cytokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], IL-1β, and IL-6) and chemokines (CXCL1, CXCL2, and CCL2). It has been reported that host defense against P. aeruginosa acute lung infection can be improved by blocking IL-1 since exaggerated IL-1β production may be harmful for the host in this infection. In agreement with these data, IL-1RI deficiency rescues the phenotype observed in Tir8-deficient mice: in Tir8?/? IL-1RI?/? double knockout mice we observed higher survival rates, enhanced bacterial clearance, and reduced levels of local and systemic cytokine and chemokine levels than in Tir8-deficient mice. These results suggest that TIR8 has a nonredundant effect in modulating the inflammation caused by P. aeruginosa, in particular, by negatively regulating IL-1RI signaling, which plays a major role in the pathogenesis of this infectious disease.
机译：Toll白介素-1受体（IL-1R）8（TIR8），也称为单Ig IL-1受体（IL-R）相关分子或SIGIRR，是IL-1R样家族的成员，主要表达通过上皮细胞。目前的证据表明，在依赖IL-R和Toll样受体（TLR）活化的不同炎症条件下，TIR8作为体内负调节剂发挥非冗余作用。在本研究中，我们检查了TIR8在对铜绿假单胞菌引起的急性肺部感染的先天性抵抗中的作用，铜绿假单胞菌是革兰氏阴性病原体，在免疫力低下的个体和囊性纤维化患者中引起威胁生命的感染。我们显示，在小鼠中，Tir8缺乏症与急性铜绿假单胞菌感染的易感性增加有关，在死亡率和细菌载量方面，与加剧促炎性细胞因子（γ干扰素[IFN-γ]，肿瘤坏死因子α的局部和全身性产生）有关。 [TNF-α]，IL-1β和IL-6）和趋化因子（CXCL1，CXCL2和CCL2）。据报道，通过阻断IL-1可以改善宿主对铜绿假单胞菌急性肺部感染的防御能力，因为过量的IL-1β产生可能对该宿主有害。与这些数据相一致，IL-1RI缺乏可以挽救在Tir8缺陷小鼠中观察到的表型：在我们观察到的Tir8 ？/？ IL-1RI ？/？双敲除小鼠中与Tir8缺陷型小鼠相比，存活率更高，细菌清除率更高，局部和全身细胞因子和趋化因子水平降低。这些结果表明，TIR8在调节由铜绿假单胞菌引起的炎症中具有非冗余作用，特别是通过负调节IL-1RI信号传导，其在该传染病的发病机理中起主要作用。

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