Browsing by Author "Corry, David B."

Now showing 1 - 5 of 5
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    Chronic exposure to carbon black ultrafine particles reprograms macrophage metabolism and accelerates lung cancer
    (AAAS, 2022) Chang, Cheng-Yen; You, Ran; Armstrong, Dominique; Bandi, Ashwini; Cheng, Yi-Ting; Burkhardt, Philip M.; Becerra-Dominguez, Luis; Madison, Matthew C.; Tung, Hui-Ying; Zeng, Zhimin; Wu, Yifan; Song, Lizhen; Phillips, Patricia E.; Porter, Paul; Knight, John M.; Putluri, Nagireddy; Yuan, Xiaoyi; Marcano, Daniela C.; McHugh, Emily A.; Tour, James M.; Catic, Andre; Maneix, Laure; Burt, Bryan M.; Lee, Hyun-Sung; Corry, David B.; Kheradmand, Farrah
    Chronic exposure to airborne carbon black ultrafine (nCB) particles generated from incomplete combustion of organic matter drives IL-17A–dependent emphysema. However, whether and how they alter the immune responses to lung cancer remains unknown. Here, we show that exposure to nCB particles increased PD-L1+ PD-L2+ CD206+ antigen-presenting cells (APCs), exhausted T cells, and Treg cells. Lung macrophages that harbored nCB particles showed selective mitochondrial structure damage and decreased oxidative respiration. Lung macrophages sustained the HIF1α axis that increased glycolysis and lactate production, culminating in an immunosuppressive microenvironment in multiple mouse models of non–small cell lung cancers. Adoptive transfer of lung APCs from nCB-exposed wild type to susceptible mice increased tumor incidence and caused early metastasis. Our findings show that nCB exposure metabolically rewires lung macrophages to promote immunosuppression and accelerates the development of lung cancer.
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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.
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    Preferential uptake of antioxidant carbon nanoparticles by T lymphocytes for immunomodulation
    (Springer Nature, 2016) Huq, Redwan; Samuel, Errol L.G.; Sikkema, William K.A.; Nilewski, Lizanne G.; Lee, Thomas; Tanner, Mark R.; Khan, Fatima S.; Porter, Paul C.; Tajhya, Rajeev B.; Patel, Rutvik S.; Inoue, Taeko; Pautler, Robia G.; Corry, David B.; Tour, James M.; Beeton, Christine; The NanoCarbon Center
    Autoimmune diseases mediated by a type of white blood cell—T lymphocytes—are currently treated using mainly broad-spectrum immunosuppressants that can lead to adverse side effects. Antioxidants represent an alternative approach for therapy of autoimmune disorders; however, dietary antioxidants are insufficient to play this role. Antioxidant carbon nanoparticles scavenge reactive oxygen species (ROS) with higher efficacy than dietary and endogenous antioxidants. Furthermore, the affinity of carbon nanoparticles for specific cell types represents an emerging tactic for cell-targeted therapy. Here, we report that nontoxic poly(ethylene glycol)-functionalized hydrophilic carbon clusters (PEG-HCCs), known scavengers of the ROS superoxide (O2•−) and hydroxyl radical, are preferentially internalized by T lymphocytes over other splenic immune cells. We use this selectivity to inhibit T cell activation without affecting major functions of macrophages, antigen-presenting cells that are crucial for T cell activation. We also demonstrate the in vivo effectiveness of PEG-HCCs in reducing T lymphocyte-mediated inflammation in delayed-type hypersensitivity and in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Our results suggest the preferential targeting of PEG-HCCs to T lymphocytes as a novel approach for T lymphocyte immunomodulation in autoimmune diseases without affecting other immune cells.
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    Targeting the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 6 (STAT6) with Cell-Permeable, Phosphatase-Stable Phosphopeptide Mimics Potently Inhibits Tyr641 Phosphorylation and Transcriptional Activity
    (American Chemical Society, 2015) Mandal, Pijus K.; Morlacchi, Pietro; Knight, J. Morgan; Link, Todd M.; Lee, Gilbert R. IV; Nurieva, Roza; Singh, Divyendu; Dhanik, Ankur; Kavraki, Lydia; Corry, David B.; Ladbury, John E.; McMurray, John S.
    Signal transducer and activator of transcription 6 (STAT6) transmits signals from cytokines IL-4 and IL-13 and is activated in allergic airway disease. We are developing phosphopeptide mimetics targeting the SH2 domain of STAT6 to block recruitment to phosphotyrosine residues on IL-4 or IL-13 receptors and subsequent Tyr641 phosphorylation to inhibit the expression of genes contributing to asthma. Structure–affinity relationship studies showed that phosphopeptides based on Tyr631 from IL-4Rα bind with weak affinity to STAT6, whereas replacing the pY+3 residue with simple aryl and alkyl amides resulted in affinities in the mid to low nM range. A set of phosphatase-stable, cell-permeable prodrug analogues inhibited cytokine-stimulated STAT6 phosphorylation in both Beas-2B human airway cells and primary mouse T-lymphocytes at concentrations as low as 100 nM. IL-13-stimulated expression of CCL26 (eotaxin-3) was inhibited in a dose-dependent manner, demonstrating that targeting the SH2 domain blocks both phosphorylation and transcriptional activity of STAT6.