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Selective Modulation of Autophagy, Innate Immunity, and Adaptive Immunity by Small Molecules

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Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
§ Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, United States
Dept. of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
# Howard Hughes Medical Institute, Cambridge, Massachusetts 02138, United States
Cite this: ACS Chem. Biol. 2013, 8, 12, 2724–2733
Publication Date (Web):October 9, 2013
Copyright © 2013 American Chemical Society

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    Autophagy is an evolutionarily conserved catabolic process that directs cytoplasmic proteins, organelles and microbes to lysosomes for degradation. Autophagy acts at the intersection of pathways involved in cellular stress, host defense, and modulation of inflammatory and immune responses; however, the details of how the autophagy network intersects with these processes remain largely undefined. Given the role of autophagy in several human diseases, it is important to determine the extent to which modulators of autophagy also modify inflammatory or immune pathways and whether it is possible to modulate a subset of these pathways selectively. Here, we identify small-molecule inducers of basal autophagy (including several FDA-approved drugs) and characterize their effects on IL-1β production, autophagic engulfment and killing of intracellular bacteria, and development of Treg, TH17, and TH1 subsets from naı̈ve T cells. Autophagy inducers with distinct, selective activity profiles were identified that reveal the functional architecture of connections between autophagy, and innate and adaptive immunity. In macrophages from mice bearing a conditional deletion of the essential autophagy gene Atg16L1, the small molecules inhibit IL-1β production to varying degrees suggesting that individual compounds may possess both autophagy-dependent and autophagy-independent activity on immune pathways. The small molecule autophagy inducers constitute useful probes to test the contributions of autophagy-related pathways in diseases marked by impaired autophagy or elevated IL-1β and to test novel therapeutic hypotheses.

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