Nearly one-third of the United States population lives in areas with unhealthy levels of ambient ozone. Since increased ozone levels are associated with respiratory problems in children, elderly, and patients with pre- existing cardiopulmonary diseases, elucidating the cellular and molecular mechanisms of ozone-induced lung injury is highly significant in terms of formulating therapeutic strategies. Ozone results in predominantly Type 2 (Th2) inflammatory responses including eosinophilic inflammation and mucous cell metaplasia that are also the hallmarks of allergic asthma. While it is understood that interleukin 4 receptor ? (IL4R?, a common receptor for IL4 and IL13) is essential for Th2 inflammatory responses, what is not clear is which IL4R?-bearing cell-type is indispensable for various outcomes in Th2-associated diseases. Lack of such knowledge is a major obstacle in the development of effective therapeutic strategies, because, without it, the IL4R? inhibitors will remain non- specific and not fully effective, as is the case with ongoing clinical trials with IL4R? inhibitors. Our central hypothesis is that myeloid cell-specific Type II IL4R is essential for ozone-induced granulocyte recruitment and the pathological manifestation of Th2-associated responses, and that the IL4R?-bearing myeloid cells release IL4 that regulates downstream IL4R? signaling through Type I IL4R? on non-myeloid cells. The overall objective of this proposal is to delineate the myeloid cell-specific role of IL4R? signaling in ozone- induced airway disease and to identify myeloid-IL4R?-mediated soluble and vesicle-bound mediators of ozone-induced inflammation in airspaces.
In aim 1 we will employ myeloid-, macrophage-, and cDC-specific IL4R? deficient mice or myeloid-only-, macrophage-only-, and cDC-only-IL4R? sufficient mice, to investigate the role of myeloid-, macrophage-, and cDC-specific IL4R? in ozone-induced granulocyte recruitment.
In aim 2, we will test our hypothesis that mye-specific IL4R? is required for IL4 production that, in turn, mediates the downstream responses through Type I IL4R?-receptor on non-myeloid cells. Furthermore, a comprehensive analysis of bronchoalveolar lavage, both fluid and the vesicular fraction, will be performed to reveal the identity of additional mediators released from IL4R?-bearing myeloid and non-myeloid cells.
In aim 3, The myeloid- specific IL4R? deficient mice (males vs females; neonates vs adults vs aged) will be exposed to ozone as well as ozone superimposed with mixed allergens.
This aim will reveal gender- and age-specific role of myeloid IL4R? in asthma outcomes. The findings from our studies will have a transformative impact on the mechanistic understanding of the pathophysiology of ozone-induced airway disease. Eventually, these findings may be applied towards the development of cell-specific therapeutics against ozone-induced as well as other Th2- associated diseases.

Public Health Relevance

Nearly one-third of the United States population lives in areas with unhealthy levels of ambient ozone, causing respiratory problems in children, elderly, and patients with pre-existing cardiopulmonary diseases. Ozone results in predominantly Type 2 (Th2) inflammatory responses including eosinophilic inflammation and mucous cell metaplasia that are also the hallmarks of allergic asthma. Using innovative approaches, supported by our novel and exciting data, we will attempt identification of a key cell-type(s) involved in the pathogenic manifestation of ozone-induced Th2 inflammation and thus, amenable for targeting of Th2 pathways in ozone- induced airway diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES030125-03
Application #
10091437
Study Section
Special Emphasis Panel (ZES1)
Program Officer
Nadadur, Srikanth
Project Start
2019-02-01
Project End
2024-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Louisiana State University A&M Col Baton Rouge
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
075050765
City
Baton Rouge
State
LA
Country
United States
Zip Code
70803