Peripheral immune tolerance mechanisms ensure immune homeostasis in the respiratory mucosa, defects in which can elicit multiple immune-mediated diseases such as asthma. Antigen presenting cells (APCs) play a central role in the decision-making process between immune activation versus tolerance. It is, therefore, important to understand the molecular mechanisms by which APCs such as dendritic cells (DCs) mediate immune tolerance to be able to use the full potential of these cells for suppression of undesirable immune activation. In our recently published study, we showed an important role for CD103+ DCs in promoting immune tolerance in the airways, these DCs having the unique ability among all the different DC subsets to express retinaldehyde dehydrogenease (aldh1a2), the key enzyme for the production of retinoic acid (RA), which is a potent cofactor for TGF-? for de novo induction of Foxp3 in T cells. Also, we have identified a novel communication axis between the nuclear receptor, PPAR?, and mitochondrial respiration triggering increased H2O2 levels in the APCs, which helps maintain immune suppression. Conditional deletion of PPAR? in CD11c cells was found to abolish the ability to induce regulatory T cells (Tregs) and IL-10 production when mice were subjected to tolerizing conditions. Unlike non-APCs in the lung, the APCs were found to harbor high levels of free polyunsaturated fatty acids (PUFAs) in the cells and, when the mouse were tolerized, the PUFA levels decreased with concomitant upregulation of the key protein for mitochondrial transport, Cpt1, in PPAR?- sufficient but not-deficient APCs. Collectively, these data allow us to hypothesize APCs express specific proteins that favor accumulation of high levels of PUFA, which undergo fatty acid oxidation (FAO) to promote tolerance. Inhibition of fatty acid translocation to mitochondria by deleting the key rate limiting enzyme, Cpt1, would be deleterious for tolerance and conversely enhancing translocation of free fatty acids to mitochondria would be a novel therapeutic approach to treat steroid-refractory asthma. This hypothesis will be tested in 3 Specific Aims in which we will: 1. Determine expression of key proteins involved in fatty acid accumulation in DCs and assess fatty acid oxidation under conditions of tolerance versus inflammation. 2. Demonstrate that mitochondrial fatty acid oxidation plays an essential role in airway tolerance promotion of which will ameliorate severe asthma in an experimental model. 3. Determine the fatty acid metabolism signature of human peripheral blood DCs in asthmatics and study DC-T cell interactions to assess inflammatory IL-10-inducing potential. The proposed study will establish a novel mechanism by which DCs regulate immune function and will also identify candidates for therapeutic intervention of difficult to treat diseases such as severe asthma.

Public Health Relevance

The goal of this application is to understand interactions between dendritic cells and T cells involving mitochondrial bioenergetics that induces immune tolerance preventing airway diseases such as asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048927-19
Application #
9422657
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Minnicozzi, Michael
Project Start
2001-01-01
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
19
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Oriss, Timothy B; Raundhal, Mahesh; Morse, Christina et al. (2017) IRF5 distinguishes severe asthma in humans and drives Th1 phenotype and airway hyperreactivity in mice. JCI Insight 2:
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Khare, Anupriya; Chakraborty, Krishnendu; Raundhal, Mahesh et al. (2015) Cutting Edge: Dual Function of PPAR? in CD11c+ Cells Ensures Immune Tolerance in the Airways. J Immunol 195:431-5

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