Agonistic induction of PPARγ reverses cigarette smoke-induced emphysema
Agonistic induction of PPARγ reverses cigarette smoke-induced emphysema
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DOI：
10.1172/jci70587
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发表时间：
2014-03-01
影响因子：
15.9
通讯作者：
Kheradmand, Farrah
中科院分区：
文献类型：
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作者：
Shan, Ming;You, Ran;Kheradmand, Farrah
暴露于香烟烟雾的人类和小鼠中肺气肿的发展通过激活适应性免疫应答而促进。来自吸烟者的肺髓样树突状细胞（mDC）激活自身反应性Th 1和Th 17细胞。T细胞亚群的mDC依赖性活化需要编码骨桥蛋白（OPN）的SPP 1基因的表达，骨桥蛋白是一种涉及自身免疫应答的多效性细胞因子。促进SPP 1表达和激活mDCs以响应烟雾的上游分子事件仍然未知。在这里，我们发现，过氧化物酶体增殖物激活受体γ（PPARG/Pparg）表达下调mDCs的吸烟者肺气肿和小鼠暴露于慢性烟雾。使用Cd 11 c-Cre Pparg（flox/flox）小鼠条件性敲除APC中的PPAR γ导致自发性肺部炎症和肺气肿，其类似于烟雾暴露小鼠的表型。Cd 11 c-Cre Pparg（flox/flox）小鼠的炎症表型需要OPN，这表明了一种炎症机制，其中PPARy负调节肺中Spp 1的表达。尽管持续暴露于烟雾中，但用PPAR γ激动剂治疗2个月可逆转WT小鼠的肺气肿。此外，内源性过氧化物酶体增殖体激活物受体γ激动剂减少吸烟者的血浆与肺气肿。这些发现揭示了一种促炎途径，其中降低的PPAR γ活性促进肺气肿，并表明在吸烟者中靶向该途径可以预防和逆转肺气肿。
The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator-activated receptor gamma (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPAR gamma in APCs using Cd11c-Cre Pparg(flox/flox) mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Pparg(flox/flox) mice required OPN, suggesting an antiinflammatory mechanism in which PPARy negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPAR gamma agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPAR gamma agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPAR gamma activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema.