A lingering conundrum of the immune response is how do certain immune/inflammatory cells """"""""remember"""""""" whether or not they should be actively transcribing specific genes, which would facilitate their participation in a given inflammatory response. Our laboratory is investigating novel epigenetic changes, induced via post- translational modifications of histones, as mechanisms to regulate the expression profiles of immune cell derived mediators, during the initiation and maintenance of lung inflammation. We have found that in the presence of either Th1 or Th2 type cytokines dynamic acetylation and/or methylation events occur at the amino terminus of histones H3 and H4, which directly regulate chromatin structures dictating the accessibility of transcription factors to specific promoters. In this application we will utilize established models of lung inflammation, which possess a distinct Th1 or Th2 phenotype, to investigate cytokine-directed, novel epigenetic-based mechanisms that direct the immune cell phenotype in support of lung pathology. Our preliminary data support a key role for epigenetic mechanisms in maintaining the inflammatory phenotype. We hypothesize that during the maintenance of pulmonary disease, a polarized cytokine environment that dictates the phenotype of specific immune cell subpopulations directly induces specific epigenetic changes in the cells, which in turn maintain cell specific transcription program required for disease chronicity. This hypothesis will be investigated via the following specific aims: 1) To investigate cell specific epigenetic changes, which are governed by the dominant cytokine environment associated with a Th1 or a Th2 type pulmonary immune response, 2) To examine the mechanistic role of the histone methyl transferase, MLL, and the histone demethylase, JMJD3, on the development of a Th1 or Th2 dependent pulmonary inflammation using conditional knockout mouse models, and 3) To assess the cytokine-induced JAK-STAT signal transduction pathways that control MLL and JMJD3 expression and influence the subsequent immune response. Our proposed studies provide an innovative approach by assessing the epigenetic-based mechanisms that control the sustained inflammatory phenotype associated with chronic lung inflammation and provide an opportunity for the development of new biomarkers and novel, efficacious therapies.
of our proposed studies is to demonstrate that the inflammatory cytokine environment directs the epigenetic-dependent molecular mechanisms which subsequently initiates and maintains the production of immune cell-derived mediators. These studies will provide an avenue for the generation of novel scientific knowledge into how the cytokine environment associated with inflammation in the lungs dictates epigenetic changes that ultimately lead to sustained expression of key mediators of immune responses. It will also provide a potential avenue for the development of new biomarkers and novel, efficacious therapies for chronic immunological disorders.
|Kimball, Andrew S; Joshi, Amrita; Carson 4th, William F et al. (2017) The Histone Methyltransferase MLL1 Directs Macrophage-Mediated Inflammation in Wound Healing and Is Altered in a Murine Model of Obesity and Type 2 Diabetes. Diabetes 66:2459-2471|
|Carson 4th, William F; Cavassani, Karen A; Soares, Elyara M et al. (2017) The STAT4/MLL1 Epigenetic Axis Regulates the Antimicrobial Functions of Murine Macrophages. J Immunol 199:1865-1874|
|Aoyagi, T; Newstead, M W; Zeng, X et al. (2017) IL-36 receptor deletion attenuates lung injury and decreases mortality in murine influenza pneumonia. Mucosal Immunol 10:1043-1055|
|Kimball, Andrew S; Joshi, Amrita D; Boniakowski, Anna E et al. (2017) Notch Regulates Macrophage-Mediated Inflammation in Diabetic Wound Healing. Front Immunol 8:635|
|Carson 4th, William F; Salter-Green, Sarah E; Scola, Melissa M et al. (2017) Enhancement of macrophage inflammatory responses by CCL2 is correlated with increased miR-9 expression and downregulation of the ERK1/2 phosphatase Dusp6. Cell Immunol 314:63-72|
|Sung Hsieh, Hsiao Hsin; Chung, Michael T; Allen, Ronald M et al. (2017) Evaluation of Salivary Cytokines for Diagnosis of both Trauma-Induced and Genetic Heterotopic Ossification. Front Endocrinol (Lausanne) 8:74|
|Kovach, M A; Singer, B; Martinez-Colon, G et al. (2017) IL-36? is a crucial proximal component of protective type-1-mediated lung mucosal immunity in Gram-positive and -negative bacterial pneumonia. Mucosal Immunol 10:1320-1334|
|Bermick, Jennifer R; Lambrecht, Nathalie J; denDekker, Aaron D et al. (2016) Neonatal monocytes exhibit a unique histone modification landscape. Clin Epigenetics 8:99|
|Ito, Toshihiro; Itakura, Junya; Takahashi, Sakuma et al. (2016) Sprouty-Related Ena/Vasodilator-Stimulated Phosphoprotein Homology 1-Domain-Containing Protein-2 Critically Regulates Influenza A Virus-Induced Pneumonia. Crit Care Med 44:e530-43|
|Suresh, Madathilparambil V; Thomas, Bivin; Machado-Aranda, David et al. (2016) Double-Stranded RNA Interacts With Toll-Like Receptor 3 in Driving the Acute Inflammatory Response Following Lung Contusion. Crit Care Med 44:e1054-e1066|
Showing the most recent 10 out of 23 publications