Broad-spectrum inflammasome inhibition by thiomuscimol.

Inflammasome formation, arising from pathogen or internal activating signals, is a key step in canonical pyroptosis, a gasdermin-mediated inflammatory cell death. Inhibition of pyroptosis has great clinical relevance due to its involvement in many different disease states. Current inhibitors of pyroptosis either only inhibit the final lytic step, which still allows inflammatory signal release, or only inhibit a single inflammasome, which does not account for inherent redundancy in activation of other inflammatory pathways.

Muscimol inhibits plasma membrane rupture and ninjurin-1 oligomerization during pyroptosis.

Pyroptosis is a cell death process that causes inflammation and contributes to numerous diseases. Pyroptosis is mediated by caspase-1 family proteases that cleave the pore-forming protein gasdermin D, causing plasma membrane rupture and release of pathogenic cellular contents. We previously identified muscimol as a small molecule that prevents plasma membrane rupture during pyroptosis via an unidentified mechanism.

Monitoring Calcium Fluxes and Lysosome Exocytosis During Pyroptosis.

Inflammasome-mediated activation of inflammatory caspases (caspase-1, caspase-4, caspase-5, caspase-11) initiates a cascade of cellular events that lead to proinflammatory cell death, or pyroptosis. Proteolytic cleavage of gasdermin D results in the formation of transmembrane pores that allow the release of mature cytokines IL-1β and IL-18. Gasdermin pores also allow calcium influx through the plasma membrane, triggering the fusion of lysosomal compartments with the cell surface and release of their contents into the extracellular milieu in a process termed lysosome exocytosis.

Failure of CD4 T Cell-Deficient Hosts To Control Chronic Nontyphoidal Infection Leads to Exacerbated Inflammation, Chronic Anemia, and Altered Myelopoiesis.

Immunocompromised patients are more susceptible to recurrent nontyphoidal (NTS) bacteremia. A key manifestation of HIV infection is the loss of CD4 T cells, which are crucial for immunity to infection. We characterized the consequences of CD4 T cell depletion in mice where virulent establish chronic infection, similar to chronic NTS disease in humans.