TNF receptor signaling contributes to chemokine secretion, inflammation, and respiratory deficits during Pneumocystis pneumonia
TNF receptor signaling contributes to chemokine secretion, inflammation, and respiratory deficits during Pneumocystis pneumonia
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DOI：
10.4049/jimmunol.172.4.2511
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发表时间：
2004-02-15
影响因子：
4.4
通讯作者：
Gigliotti, F
中科院分区：
文献类型：
--
作者：
Wright, TW;Pryhuber, GS;Gigliotti, F
在艾滋病相关疾病的小鼠模型中，CD 8（+）T细胞参与肺孢子虫肺炎（PcP）的病理生理学。本研究旨在更精确地确定这些免疫细胞介导导致肺损伤的炎症反应的机制。实验小鼠耗尽CD 4（+）T细胞或CD 4（+）和CD 8（+）T细胞，然后感染肺孢子虫。CD 4（+）耗竭小鼠的肺TNF-α水平显著高于CD 4（+）和CD 8（+）T细胞耗竭小鼠。TNF-α水平升高与趋化因子RANTES、单核细胞趋化蛋白1、巨噬细胞炎性蛋白2和尼古丁诱导的中性粒细胞趋化因子的肺浓度升高相关。为了确定TNFR信号是否参与CD 8（+）T细胞依赖性趋化因子应答，将TNFRI-和II-缺陷小鼠CD 4（+）耗竭并感染肺孢子虫。与感染的野生型小鼠相比，TNFR缺陷型小鼠的肺部RANTES、单核细胞趋化蛋白1、巨噬细胞炎性蛋白2和尼古丁诱导的中性粒细胞趋化反应显著降低，肺泡炎性细胞募集减少，PcP相关性肺泡炎的组织学证据减少。在TNFR缺陷小鼠中，肺部炎症减少与表面活性剂活性改善和肺功能改善相关。这些数据表明，TNFR信号传导是最大的CD 8（+）T细胞依赖性肺部炎症和肺损伤在PcP过程中所必需的，也证明了CD 8（+）T细胞可以使用TNFR信号传导途径来响应细胞外真菌病原体。免疫学杂志，2004，172：2511-2521.
CD8(+) T cells contribute to the pathophysiology of Pneumocystis pneumonia (PcP) in a murine model of AIDS-related disease. The present studies were undertaken to more precisely define the mechanisms by which these immune cells mediate the inflammatory response that leads to lung injury. Experimental mice were depleted of either CD4(+) T cells or both CD4(+) and CD8(+) T cells and then infected with Pneumocystis. The CD4(+)-depleted mice had significantly greater pulmonary TNF-alpha levels than mice depleted of both CD4(+) and CD8(+) T cells. Elevated TNF-alpha levels were associated with increased lung concentrations of the chemokines RANTES, monocyte chemoattractant protein 1, macrophage-inflammatory protein 2, and cytokine-induced neutrophil chemoattractant. To determine whether TNFR signaling was involved in the CD8(+) T cell-dependent chemokine response, TNFRI- and II-deficient mice were CD4(+) depleted and infected with Pneumocystis. TNFR-deficient mice had significantly reduced pulmonary RANTES, monocyte chemoattractant protein 1, macrophage-inflammatory protein 2, and cytokine-induced neutrophil chemoattractant responses, reduced inflammatory cell recruitment to the alveoli, and reduced histological evidence of PcP-related alveolitis as compared with infected wild-type mice. Diminished pulmonary inflammation correlated with improved surfactant activity and improved pulmonary function in the TNFR-deficient mice. These data indicate that TNFR signaling is required for maximal CD8(+) T cell-dependent pulmonary inflammation and lung injury during PcP and also demonstrate that CD8(+) T cells can use TNFR signaling pathways to respond to an extracellular fungal pathogen. The Journal of Immunology, 2004, 172: 2511-2521.