Donald A. Cohen, Ph.D.

Professor

Selected publications

Research statement: Inflammation in various organs can be caused by a variety of factors, including infectious agents, autoimmunity, environmental pollutants and therapeutic modalities. Regardless of the cause, the failure to adequately regulate the inflammatory response can lead to persistent inflammation and the development of structural changes in tissue architecture that can affect normal function in the inflamed tissue. Research in this laboratory is focused on understanding immunological mechanisms which regulate the onset and persistence of inflammation in acute and chronic disease settings.

I. Interleukin -10 Receptor Function in Lung Inflammation. Efficient regulation of inflammation in the lungs is essential not only to allow for rapid mobilization of inflammatory cells during infection, but also to prevent inflammation during exposure of the lungs to innocuous substances. Normal homeostatic conditions in the lungs are generally thought to be immunosuppressive, due in part to alveolar macrophages (AM) which can release inhibitory factors including nitric oxide, prostaglandins, transforming growth factor and interleukin-10 (IL-10). Binding of IL-10 to IL-10 receptors on AM dramatically inhibits the production of proinflammatory cytokines, IL-1, IL-6, IL-8 and TNF ". However, we have shown that under inflammatory conditions, AM become hyporesponsive to IL-10 in that synthesis of TNF " and IL-6 cannot be effectively inhibited by IL-10. Bronchoalveolar epithelial cells (EpC) also have been shown to constitutively release IL-10, but to loose that capacity during inflammatory conditions. We are investigating the hypothesis that under normal homeostatic conditions in the lung, an inhibitory loop is active in which constitutively produced IL-10 by EpC acts on AM to prevent inappropriate synthesis of proinflammatory cytokines. Following exposure to infectious microorganisms, the homeostatic production of IL-10 by EpC and/or the response of the IL-10 receptors on AM are rapidly diminished via signaling through pattern recognition receptors on EpC and AM. Induction of proinflammatory cytokines in the lungs is thus more efficiently induced by microbial rather than by non-microbial substances. Using in vivo murine models and cell culture models, we are evaluating the following: 1.) What changes are induced in the synthesis of IL-10 by alveolar epithelial cells and in IL-10 receptor function on alveolar macrophages by microbial and non-microbial stimuli? 2.) Is induction of IL-10 hyporesponsiveness in alveolar macrophages mediated via pattern recognition receptors, including Toll-like receptors and phagocytic receptors? 3.) Is IL-10 receptor hyporesponsiveness mediated directly via inhibition of signal transduction pathways or indirectly via synthesis of inhibitory molecules such as “suppressors of cytokine signaling” (SOCS)? 4.) How can Toll-like receptor signaling induce IL-10 receptor hyporesponsiveness?  

II. Contribution of Macrophages to the Development of Experimental Colitis. Inflammatory bowel disease (IBD) is a severe chronic inflammation of the intestinal tract that affects over 1.4 million people in the U.S. The role of individual types of immune cells in the development of IBD remains a hotly debated topic and the role of macrophages, in particular, in IBD remains uncertain. Macrophages play multiple roles during an inflammatory response. First, macrophages present in the tissue are involved in initiating an inflammatory response by engulfing inflammatory stimuli and then releasing factors which call in additional immune cells to the tissue site. Secondly, additional macrophages arrive at the tissue site from the blood, thus amplifying inflammation. Finally, when the inflammatory stimulus is removed, macrophages then release a variety of factors that aid in the healing process in the injured tissue. Much of the difficult in evaluating the role of macrophages has been the inability to selectively deplete macrophages in the colon in animal models of colitis. We have developed a new transgenic mouse line (MaFIA) in which macrophages can be systemically depleted following activation of the transgene. Using this new transgenic mouse line and an additional method to deplete macrophages in the colon, we have shown that intestinal macrophages play a protective role in the development and progression of dextran sodium sulfate (DSS)-induced colitis. Removal of macrophages from the colon leads to more severe colitis, associated with an increase in neutrophil infiltration into colonic tissues. Studies are underway to investigate the mechanisms by which macrophages control the inflammatory response in this disease model. Understanding the role that macrophages play in the development of colitis will allow a better determination of whether macrophages should be considered a therapeutic target in patients with inflammatory bowel disease.