Browsing by Author "Lu, Wen"

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    The microRNA miR-22 inhibits the histone deacetylase HDAC4 to promote TH17 cell–dependent emphysema
    (Nature Publishing Group, 2015) Lu, Wen; You, Ran; Yuan, Xiaoyi; Yang, Tianshu; Samuel, Errol L.G.; Marcano, Daniela C.; Sikkema, William K.A.; Tour, James M.; Rodriguez, Antony; Kheradmand, Farrah; Corry, David B.
    Smoking-related emphysema is a chronic inflammatory disease driven by the T(H)17 subset of helper T cells through molecular mechanisms that remain obscure. Here we explored the role of the microRNA miR-22 in emphysema. We found that miR-22 was upregulated in lung myeloid dendritic cells (mDCs) of smokers with emphysema and antigen-presenting cells (APCs) of mice exposed to smoke or nanoparticulate carbon black (nCB) through a mechanism that involved the transcription factor NF-κB. Mice deficient in miR-22, but not wild-type mice, showed attenuated T(H)17 responses and failed to develop emphysema after exposure to smoke or nCB. We further found that miR-22 controlled the activation of APCs and T(H)17 responses through the activation of AP-1 transcription factor complexes and the histone deacetylase HDAC4. Thus, miR-22 is a critical regulator of both emphysema and T(H)17 responses.
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    Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema
    (eLife Sciences Publications Ltd., 2015) You, Ran; Lu, Wen; Shan, Ming; Berlin, Jacob M.; Samuel, Errol L.G.; Marcano, Daniela C.; Sun, Zhengzong; Sikkema, William K.A.; Yuan, Xiaoyi; Song, Lizhen; Hendrix, Amanda Y.; Tour, James M.; Corry, David B.; Kheradmand, Farrah
    Chronic inhalation of cigarette smoke is the major cause of sterile inflammation and pulmonary emphysema. The effect of carbon black (CB), a universal constituent of smoke derived from the incomplete combustion of organic material, in smokers and non-smokers is less known. In this study, we show that insoluble nanoparticulate carbon black (nCB) accumulates in human myeloid dendritic cells (mDCs) from emphysematous lung and in CD11c+ lung antigen presenting cells (APC) of mice exposed to smoke. Likewise, nCB intranasal administration induced emphysema in mouse lungs. Delivered by smoking or intranasally, nCB persisted indefinitely in mouse lung, activated lung APCs, and promoted T helper 17 cell differentiation through double-stranded DNA break (DSB) and ASC-mediated inflammasome assembly in phagocytes. Increasing the polarity or size of CB mitigated many adverse effects. Thus, nCB causes sterile inflammation, DSB, and emphysema and explains adverse health outcomes seen in smokers while implicating the dangers of nCB exposure in non-smokers.