The IκB family member Bcl-3 coordinates the pulmonary defense against Klebsiella pneumoniae infection.
The IκB family member Bcl-3 coordinates the pulmonary defense against Klebsiella pneumoniae infection.
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DOI：
10.4049/jimmunol.1001331
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发表时间：
2011-02-15
期刊：
影响因子：
--
通讯作者：
Siebenlist U
中科院分区：
文献类型：
--
作者：
Pène F;Paun A;Sønder SU;Rikhi N;Wang H;Claudio E;Siebenlist U
Bcl-3是IκB家族的一个非典型成员，具有以环境依赖性方式正向或负向调节核NF-κB活性的潜力。Bcl-3的生物学影响是复杂的，包括在肿瘤发生和多种免疫反应中的作用，包括先天免疫。Bcl-3可能介导LPS耐受，抑制细胞因子的产生，但它似乎也有助于防御选择的全身性细菌的挑战。然而，Bcl-3在器官特异性宿主防御细菌中的潜在作用尚未得到解决。在这里，我们调查的相关性Bcl-3在肺部挑战革兰氏阴性病原体肺炎克雷伯氏菌。与野生型小鼠相比，Bcl-3缺陷型小鼠对K.肺炎突变小鼠表现出以嗜酸性肺泡实变为标志的肺损伤增加，并且它们未能清除肺中的细菌，这与增加的菌血症传播相关。Bcl-3的缺失导致肺中显著的细胞因子失衡，其特征在于更高水平的IL-10和几乎完全缺乏IFNγ。此外，Bcl-3缺陷型小鼠的肺部产生的趋化因子CXCL-1和CXCL-2增加。肺泡巨噬细胞和中性粒细胞在肺的抗菌防御中起重要作用。用LPS或热灭活的K. pneumoniae的表达再现了IL-10产生的增加，并且Bcl-3缺陷的中性粒细胞在细胞内细菌杀伤中受损。这些发现表明，Bcl-3在肺防御革兰氏阴性菌，调节几个细胞的功能，以促进有效清除细菌的关键参与。
Bcl-3 is an atypical member of the IκB family that has the potential to positively or negatively modulate nuclear NF-κB activity in a context-dependent manner. Bcl-3's biologic impact is complex and includes roles in tumorigenesis and diverse immune responses, including innate immunity. Bcl-3 may mediate LPS tolerance, suppressing cytokine production, but it also appears to contribute to defense against select systemic bacterial challenges. However, the potential role of Bcl-3 in organ-specific host defense against bacteria has not yet been addressed. Here we investigate the relevance of Bcl-3 in a lung challenge with the Gram-negative pathogen Klebsiella pneumoniae. In contrast to wild-type mice, Bcl-3 deficient mice exhibited significantly increased susceptibility towards K. pneumoniae pneumonia. The mutant mice showed increased lung damage marked by neutrophilic alveolar consolidation and they failed to clear bacteria in lungs, which correlated with increased bacteremic dissemination. Loss of Bcl-3 incurred a dramatic cytokine imbalance in the lungs characterized by higher levels of IL-10 and a near total absence of IFNγ. Moreover, Bcl-3 deficient mice displayed increased lung production of the neutrophil-attracting chemokines CXCL-1 and CXCL-2. Alveolar macrophages and neutrophils are important to antibacterial lung defense. In vitro stimulation of Bcl-3-deficient alveolar macrophages with LPS or heat-killed K. pneumoniae recapitulated the increase in IL-10 production and Bcl-3 deficient neutrophils were impaired in intracellular bacterial killing. These findings suggest that Bcl-3 is critically involved in lung defense against Gram-negative bacteria, modulating functions of several cells to facilitate efficient clearing of bacteria.
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