The risk of respiratory diseases increases significantly with advancing age. Elderly people are more prone to lung infections such as influenza and pneumonia and chronic illnesses such as asthma and obstructive pulmonary disease. The underlying mechanisms are not well understood. Airways are continuously being exposed to a wide variety of inhaled antigens majority of which are harmless. Dendritic cells (DCs) are key innate immune cells which are critical for initiation and generation of an effective immune response against invading pathogens as well as for maintaining tolerance against harmless inhaled antigens. Vitamin A metabolite, Retinoic acid (RA) plays a major role in inducing tolerance in respiratory DCs. Our preliminary data suggests that DCs from aged subjects are impaired in their response to retinoic acid resulting in loss of tolerance. Furthermore, aged DCs also affect the functions of airway epithelial cells to induce the secretion of various chemokines such as CXCL-10, CCL-26, and CCL-20 which can attract other cells into the airways and enhance inflammation. Therefore, we hypothesize that DCs from aged are impaired in their capacity to maintain tolerance at the respiratory surfaces which results in chronic inflammation and remodeling of the airways and increases the susceptibility of the elderly to respiratory illnesses.
Our specific aims for the proposal are -1) to investigate the mechanisms responsible for impaired response of DCs from elderly to RA;2) to determine the functional consequences of reduced RA metabolism in aged DCs;3) to investigate the effect of altered RA response of aged DC on DC-epithelial cell crosstalk. Aged population is increasing worldwide and a better understanding of the mechanisms underlying the increased susceptibility of the elderly to respiratory diseases is required for design of novel and more effective treatment.

Public Health Relevance

Dendritic cells (DC) are specialized white blood cells that control the body's ability to respond to infections and at the same time prevent immune response to harmless antigens in the air and food. We have discovered that DCs from elderly respond to harmless antigens and cause inflammation in lung which leads to increase in respiratory diseases in the elderly. Our goal is to understand why this happens and how it changes the immune response of the elderly to respiratory infections. This may help identify novel targets for therapeutic interventions for treatment of respiratory diseases in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG045216-01A1
Application #
8694995
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Fuldner, Rebecca A
Project Start
2014-09-30
Project End
2019-04-30
Budget Start
2014-09-30
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Irvine
State
CA
Country
United States
Zip Code
92697
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