Friday, September 22, 2023
9/22/2023
Project Summary 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 a (IL4Ra, a common receptor for IL4 and IL13) is essential for Th2 inflammatory responses, what is not clear is which IL4Ra-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 IL4Ra inhibitors will remain non- specific and not fully effective, as is the case with ongoing clinical trials with IL4Ra 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 IL4Ra-bearing myeloid cells release IL4 that regulates downstream IL4Ra signaling through Type I IL4Ra on non-myeloid cells. The overall objective of this proposal is to delineate the myeloid cell-specific role of IL4Ra signaling in ozone- induced airway disease and to identify myeloid-IL4Ra-mediated soluble and vesicle-bound mediators of ozone-induced inflammation in airspaces. In aim 1 we will employ myeloid-, macrophage-, and cDC-specific IL4Ra deficient mice or myeloid-only-, macrophage-only-, and cDC-only-IL4Ra sufficient mice, to investigate the role of myeloid-, macrophage-, and cDC-specific IL4Ra in ozone-induced granulocyte recruitment. In aim 2, we will test our hypothesis that mye-specific IL4Ra is required for IL4 production that, in turn, mediates the downstream responses through Type I IL4Ra-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 IL4Ra-bearing myeloid and non-myeloid cells. In aim 3, The myeloid- specific IL4Ra 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 IL4Ra 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.
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