Type-I IFN Signaling Suppresses an Excessive IFN-γ Response and Thus Prevents Lung Damage and Chronic Inflammation During Pneumocystis (PC) Clearance in CD4 T Cell-Competent Mice
Type-I IFN Signaling Suppresses an Excessive IFN-γ Response and Thus Prevents Lung Damage and Chronic Inflammation During Pneumocystis (PC) Clearance in CD4 T Cell-Competent Mice
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DOI：
10.2353/ajpath.2010.091158
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发表时间：
2010-06-01
影响因子：
6
通讯作者：
Harmsen, Allen G.
中科院分区：
文献类型：
--
作者：
Meissner, Nicole;Swain, Steve;Harmsen, Allen G.
高效抗逆转录病毒治疗（HAART）后的免疫重建通常是不完整的，一些hiv感染者不能再生产生i型干扰素（IFN）的pDCs。我们最近证明，在CD4 T细胞胜任小鼠感染肺囊虫（PC）期间，尽管清除，i型IFN信号的缺乏导致慢性肺部炎症和纤维化。由于所涉及的机制尚不清楚，我们进一步表征了i型IFN信号在PC免疫应答中的作用。我们发现，感染后第7天左右的i型IFN信号对炎症的结果至关重要。肺CD11c（+）细胞的芯片分析显示，在感染后第7天，野生型细胞上调i型IFN应答基因以及SOCS1， SOCS1是i型IFN和IFN- γ信号的关键负调节因子。这与嗜酸性肺炎症、PC清除和完全恢复有关。然而，来自IFNAR（-/-）小鼠的肺CD11c（+）细胞在第7天表现出肿瘤坏死因子(TNE)- α产生增加，缺乏socs1诱导。随后是短暂的淋巴细胞和ifn - γ反应，然后转变为慢性肺嗜酸性粒细胞炎症。早期中和tnf - α并不能预防IFNAR（-/-）小鼠的慢性炎症，但用抗ifn - γ抗体治疗可以。我们提出，在PC肺部感染期间，i型ifn诱导socs1相关的调节机制，从而防止过度的ifn - γ介导的反应导致慢性肺损伤。因此，由于i型干扰素作用减少，艾滋病患者的部分免疫重建可能会破坏炎症的调节方面，导致无法解释的慢性肺部并发症，如在一些接受HAART治疗的患者中所见。（美国病理学杂志，2010,176:2806-2818;DOI: 10.2353/ajpath.2010.091158）
Immune-reconstitution after highly active antiretroviral therapy (HAART) is often incomplete, and some HIV-infected individuals fail to regenerate type-I interferon (IFN)-producing pDCs. We recently demonstrated that during Pneumocystis (PC) infection in CD4 T cell-competent mice the absence of type-I IFN signaling results in chronic pulmonary inflammation and fibrosis despite clearance. Because the mechanisms involved are poorly understood, we further characterized the role of type-I IFN signaling in immune responses to PC. We show that type-I IFN signaling around day 7 postinfection is critical to the outcome of inflammation. Microarray analysis of pulmonary CD11c(+) cells revealed that at day 7 post infection, wild-type cells up-regulated type-I IFN-responsive genes as well as SOCS1, which is a critical negative-regulator of type-I IFN and IFN-gamma signaling. This was associated with an eosinophilic lung inflammation, PC clearance, and complete restitution. However, pulmonary CD11c(+) cells from IFNAR(-/-) mice demonstrated increased tumor necrosis factor (TNE)-alpha production and lacked SOCS1-induction at day 7. This was followed by a transient lymphocytic and IFN-gamma response before switching to a chronic eosinophilic inflammation of the lung. Early neutralization of TNF-alpha did not prevent chronic inflammation in IFNAR(-/-) mice, but treatment with an anti-IFN-gamma antibody did. We propose that during PC lung infection type-I IFNs induce SOCS1-associated regulatory mechanisms, which prevent excessive IFN-gamma-mediated responses that cause chronic lung damage. Therefore, partial immune-reconstitution in AIDS, attributable to reduced type-I IFN actions, might disrupt regulatory aspects of inflammation, causing unexplained chronic pulmonary complications as seen in some patients during HAART. (Am J Pathol 2010, 176:2806-2818; DOI: 10.2353/ajpath.2010.091158)