Study the link of autophagy dysfunction to allergic and neutrophilic asthma onset

Abstract
The long-term goal of this study is to increase our understanding of the immune mechanisms involved in the
pathogenesis of allergic diseases and asthma. Autophagy is an evolutionarily conserved and highly regulated
essential homeostatic process that ensures lysosome-dependent bulk degradation of cytosolic proteins and
organelles. Alterations in autophagy have been implicated in numerous conditions afflicting humans, including
aging, cancer, neurodegenerative processes, and immune responses, as autophagy is essential for the
generation of both innate and adaptive immune responses to pathogens. This project is motivated by recent
published data from our laboratory and others, demonstrating that abrogation of autophagy, particularly in
dendritic cells (DCs), induces severe airway hyperreactivity (AHR) in animal models (J Allergy Clin Immunol,
2016; Science. 2017). Moreover, several studies clearly demonstrate that genetic variants in Atg5, a critical
gene in autophagy, are significantly associated with childhood asthma. In support of those studies, our
preliminary results suggest that: A) treatment with autophagy inducers reduces AHR in animal models
sensitized with allergens, B) enhancement of autophagy in dendritic cells induces IL-10 and significantly up-
regulates PD-L2, which in turn robustly polarizes naïve T cells towards Foxp3+ regulatory T cells, C) genetic
ablation of autophagy, particularly in DCs, induces steroid-resistant AHR in murine models, and D) autophagy
is severely impaired in pulmonary dendritic cells obtained from patients with moderate to severe asthma. We
now propose to investigate if enhancement of autophagy, particularly among antigen presenting cells,
ameliorates pathology associated with asthma, suppresses unwanted lung inflammation and ultimately
improves lung inflammation and function. To test this hypothesis, we first designed several approaches utilizing
tissue-specific and conditional knockout murine models established in our laboratory. Second, we intend to
modulate autophagy using a novel and robust autophagy inducer that was discovered recently by our
collaborators at USC. Finally, we will extend our preliminary results in humans by assessing autophagy levels
in the bronchoalveolar fluid and peripheral blood of patients with asthma, and determine if treatment with
autophagy inducers can enhance immune-regulatory pathways. For the human studies we successfully
established collaborations with UCSF pulmonary group and will utilized their lung biopsy repository samples
obtained from well-defined cohorts of patients with asthma including neutrophilic asthma. Furthermore, we
have assembled a team of scientists including a leading expert in autophagy and the chief of clinical
pulmonology at USC to complement our laboratory's extensive experience in pre-clinical models of AHR. We
believe that the results obtained from this study will provide novel insights into an important and previously
unrecognized role of autophagy in asthma.

Grant Number: 5R01HL151493-05
NIH Institute/Center: NIH
Principal Investigator: OMID AKBARI