A major goal of this PPG is to define the cellular and molecular basis for structure, function, and remodeling of the lung epithelium. In that context, we have focused on the development of mucous cell metaplasia. In the previous cycle, we provided proof for the hypothesis that acute viral infections can permanently reprogram the immune response to drive airway epithelial cells towards chronic mucous cell metaplasia. For this renewal, we will focus on how the immune system becomes capable of regulating this type of airway epithelial cell behavior. In that regard, we have recently discovered two novel mechanisms for immune cells to persistently produce IL-13 and thereby cause chronic mucous cell metaplasia. The first mechanism is based on the capacity of acute viral infection to activate CDId-dependent invariant NKT cells that in turn drive the generation of IL-13-producing macrophages in the lung. The second mechanism depends on the capacity of viral infection to drive interferon (IFN)-dependent expression of the high-affinity IgE receptor (FcsRI) on conventional dendritic cells (cDCs) that in turn recruit IL-13-producing CD4* T helper type 2 (Th2) cells to the lung. Thus, IL-13 production and consequent mucous cell metaplasia derives from the combined contributions of persistently activated macrophages and Th2 cells. Each of these pathways appears active in patients with mucous cell metaplasia due to asthma or COPD as well. In addition to these two new pathways, we have recently discovered that a third type of immune cell population also contributes significantly to IL-13 production and consequent mucous cell metaplasia after viral infection in mice. This cell population exhibits a distinct non-B non-T (NBNT) cell lineage with high levels of MHC Class II expression. The closest known counterpart for these IL-13+MHC-H+ NBNT cells appears to be an IL-25- dependent cell population found in mouse gut after helminth infection. Others report an IL-25 requirement for the response to inhaled allergen in mice and a marked increased IL-25 and IL-25 receptor (IL-25R) expression in allergic asthma patients. Taken together, we propose a new role for the lung population of IL- 13+MHC-ir NBNT cells in chronic airway disease. The present project will determine whether this NBNT cell population found after viral infection is also driven by IL-25 and/or other factors, and how this distinct immune cell population contributes to the development of chronic airway disease in this mouse model and in patients with chronic mucous cell metaplasia due to asthma or COPD. Together, the findings should provide a comprehensive scheme for the immune pathways leading to mucous cell metaplasia in the remodeling of airway epithelium. The findings should also provide new targets for therapeutic intervention in patients with mucus obstruction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL029594-30
Application #
8378774
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
30
Fiscal Year
2012
Total Cost
$237,311
Indirect Cost
$59,579
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Holtzman, Michael J; Byers, Derek E; Alexander-Brett, Jennifer et al. (2014) The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat Rev Immunol 14:686-98
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Byers, Derek E; Alexander-Brett, Jennifer; Patel, Anand C et al. (2013) Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease. J Clin Invest 123:3967-82
Gharib, Sina A; Altemeier, William A; Van Winkle, Laura S et al. (2013) Matrix metalloproteinase-7 coordinates airway epithelial injury response and differentiation of ciliated cells. Am J Respir Cell Mol Biol 48:390-6
Tocchi, Autumn; Parks, William C (2013) Functional interactions between matrix metalloproteinases and glycosaminoglycans. FEBS J 280:2332-41

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