Targeting HMGB1 and Inflammasome Pathways: A Novel Approach to Mitigate
Inflammation in Non-Polio Enterovirus Infections
Abstract
Non-polio enteroviruses (NPEVs) are a known cause of neurological
illnesses, and in recent years, respiratory complications have been
linked to EV-D68, EV-A71, and human rhinovirus (HRV). Understanding and
identifying the molecules responsible for the inflammatory responses
associated with NPEVs is vital to targeting current therapeutic
compounds effectively. One such molecule is HMGB1, which plays a
critical role in inducing inflammation. Disulfide-HMGB1 interaction with
TLR-4 leads to the release of pro-inflammatory cytokines. Infected or
dying cells also secrete extracellular HMGB1 and innate immune
molecules. The HMGB1-RAGE axis can trigger inflammasome formation by
activating caspase-1, resulting in pyroptosis. Recent research has shown
that EV-A71 infection induces gasdermin-D, which causes perforations in
the plasma membrane and subsequent inflammasome formation and causes
pyroptosis. This cascade releases IL-1β and IL-18, leading to cell
lysis, inflammatory cell recruitment, and increased cytokine production.
However, excessive production of these cells and cytokines can lead to
severe complications, including cytokine storms that exacerbate disease
symptoms. By focusing on these key molecular targets and pathways, we
can move further to mitigate the devastating effects of uncontrolled
inflammation during viral infections, including NPEVs. The therapeutic
potential of compounds such as HMGB1 inhibitors, P2X7 receptor
antagonists, and anti-inflammatory agents like ethyl pyruvate, heparin,
glycyrrhizin, and resveratrol offers exciting avenues for future
research and clinical application.