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

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.