Lung-associated antigen presenting cells (APCs) detect innumerable toxins that enter the distal airspaces with each breath. Whether they quell or incite inflammation upon acute sensing of pollutants could be of important consequence. Specifically ineffective APC function results in immune tolerance, chronic infections, or cancer, whereas aberrant processing of antigen can induce autoimmunity. We have demonstrated that a subtype of smokers who develop emphysema harbor autoimmune inflammation, characterized by the presence of elastin- specific T helper type 1 (Th1) and Th17 cells. Antigen specific T cells induce matrix metalloproteinase (MMP) 12 secretion in the lung that inhibits alpha 1 anti-trypsin (A1AT), thereby unleashing the activity of neutrophil elastase that cleaves elastin and weakens lung parenchyma. However, the immune events leading to the activation of Th1 and Th17 cells and emphysema through cigarette smoke remain obscure. Further, even among smokers, there exists large phenotypic variability suggesting that modifier genes and environmental exposures together exert a combined effect. We have found that lung APCs isolated from mice with emphysema can induce inflammatory cytokines, and cause emphysema when transferred to na?ve mice. Gene microarray analysis of lung APCs and our additional preliminary data suggest the presence of a regulatory relationship between the aryl hydrocarbon receptor (AhR), osteopontin (SPP1), and peroxisome proliferator- activated receptor gamma (PPAR-?), an anti-inflammatory transcription factor. Therefore, we hypothesize that tobacco smoke induces Th1 and Th17 cells through unique innate and adaptive immune mechanisms operative in lung APCs. We propose using a preclinical model of emphysema to i) Determine the sentinel role of the aryl hydrocarbon receptor in APC-induced pathogenic T cell activation in emphysema, and to ii) Determine the role of PPAR-?-osteopontin in cigarette smoke-dependent APC maturation and pathogenic Th1 and Th17 cell differentiation. This application captures some of the critical initiation events in smoke-induced inflammation and applies this knowledge to explore new therapeutic options in emphysema.
In this grant application we propose to test new hypotheses that are based on our recent findings to elucidate the upstream molecular pathways that are activated in lung APCs, and could induce a vicious cycle of chronic unrelenting inflammation found in the lungs of smokers with emphysema. Further, we will provide preclinical evidence for the effectiveness of a few selected anti-inflammatory molecules in prevention and/or treatment of emphysema.
|Tung, Hui-Ying; Landers, Cameron; Li, Evan et al. (2016) Allergen-encoded signals that control allergic responses. Curr Opin Allergy Clin Immunol 16:51-8|
|Mbawuike, Innocent N; Atmar, Robert L; Patel, Shital M et al. (2016) Cell mediated immune responses following revaccination with an influenza A/H5N1 vaccine. Vaccine 34:547-54|
|Lu, Wen; You, Ran; Yuan, Xiaoyi et al. (2015) The microRNA miR-22 inhibits the histone deacetylase HDAC4 to promote T(H)17 cell-dependent emphysema. Nat Immunol 16:1185-94|
|Bhavani, Sivasubramanium; Tsai, Chu-Lin; Perusich, Sarah et al. (2015) Clinical and Immunological Factors in Emphysema Progression. Five-Year Prospective Longitudinal Exacerbation Study of Chronic Obstructive Pulmonary Disease (LES-COPD). Am J Respir Crit Care Med 192:1171-8|
|Yang, Tianshu; Lin, Qing; Zhao, Mengmeng et al. (2015) IL-37 Is a Novel Proangiogenic Factor of Developmental and Pathological Angiogenesis. Arterioscler Thromb Vasc Biol 35:2638-46|
|Mandal, Pijus K; Morlacchi, Pietro; Knight, J Morgan et al. (2015) 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. J Med Chem 58:8970-84|
|Yuan, X; Shan, M; You, R et al. (2015) Activation of C3a receptor is required in cigarette smoke-mediated emphysema. Mucosal Immunol 8:874-85|
|You, Ran; Lu, Wen; Shan, Ming et al. (2015) Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema. Elife 4:e09623|
|Bhavani, Sivasubramanium; Yuan, Xiaoyi; You, Ran et al. (2015) Loss of Peripheral Tolerance in Emphysema. Phenotypes, Exacerbations, and Disease Progression. Ann Am Thorac Soc 12 Suppl 2:S164-8|
|Chen, Min; Hong, Monica Jeongsoo; Sun, Huanhuan et al. (2014) Essential role for autophagy in the maintenance of immunological memory against influenza infection. Nat Med 20:503-10|
Showing the most recent 10 out of 14 publications