Nucleotide-binding domain (NBD) and leucine-rich repeat (LRR)-containing proteins (NLRs) assemble into
functional supramolecular organizing centers called the inflammasomes, which serve as an interface of host
defense against pathogens or other types of danger. Canonical inflammasomes activate caspase-1, an
inflammatory protease that upon activation, triggers two important biological responses: 1) processing of cytokine
interleukin-1b (IL-1b), and 2) formation of plasma membrane gasdermin D pores to potentiate inflammatory cell
death (pyroptosis). Cytokine secretion and pyroptosis are coupled under a steady-state condition, as the GSDMD
pores on the plasma membrane, which permeates IL-1b, can also compromise the cell membrane integrity
leading to the lytic cell death. Interestingly, in a hyperactive state following inflammasome activation, cells show
sustained cytokine secretion but retain viability, even though this process is dependent on GSDMD pores formed
on the plasma membrane. The underlying mechanisms which recalibrate GSDMD to only sustain the release of
the interleukin, but not pyroptosis, are poorly understood.
Autophagy is regarded as an important regulator of inflammation. In our recent studies, we found that
inflammasomes are regulated by an aggresome-like mechanism that promotes inflammasome assembly (Yang)
but also induces autophagy to dampen caspase-1 processing and IL-b secretion (Yin) (Magupalli et al., Science,
2020). Our studies are consistent with previous reports showing that mice lacking the key autophagic gene,
Atg16L1, in hematopoietic cells, were highly susceptible to dextran sulphate sodium-induced acute colitis, with
the secretion of a high amount of IL-1b
and IL-18 cytokines. In addition, these
inflammatory phenotypes were
alleviated by injection of anti-IL-1b and IL-18 antibodies in mice. Collectively, our and other published results
demonstrate that autophagy directly regulates the extent to which inflammasomes activate downstream signals.
However, it is unclear if autophagy can regulate the switch between a hyperactive state and a pyroptotic state of
In this application, we will investigate the potential link between autophagy and macrophage
hyperactivation using inflammasome assays and cellular imaging.