Inflammasome biology, molecular pathology of pyroptosis, and exploration of therapeutic implications

Inflammasomes are intracellular multiprotein signaling complexes important in host defense; however, a deregulated activity is associated with a number of inflammatory, immune and metabolic disorders. The nucleation of inflammasomes around cytoplasmic receptors of the nucleotide-binding leucine-rich repeating containing receptor (NLR) family occurs upon detection of a microbial. This results in the recruitment and activation of caspase 1 an enzyme that regulates the secretion of proinflammatory IL1B and IL18 cytokines and pyroptosis, a caspase-1 mediated form of cell death. Pyroptosis occurs through cleavage of Gasdermin D, a membrane pore forming protein. Biotherapies targeting the products of inflammasome nucleation and activation such as caspase 1 inhibitors such as Z-VAD-FMK, Ac-YVAD-cmk, and VX765, among many promising biotherapies and are explored in my studies. Lipopolysaccharide (LPS) and nigericin was introduced to THP1 macrophage like cells to induce the activation of inflammasomes and pyroptosis. Caspase 1 activation, IL1B/IL18 secretion, and cleavage of Gasdermin D were detected using western blots and ELIZA kits. From my studies, it is clear that nigericin and the subsequent activation of the NLRP3 inflammasome in addition to LPS is important in the efficacy of the caspase 1 inhibitor Ac-YVAD-cmk, the most effective inhibitor found in my studies. The exploration of caspase 1 in the NLRP3 inflammasome in common inflammatory diseases has paved the way for the use of biotherapies in the future. The success of these therapies open the door to exciting research and clinical trials in the search for an end in these inflammatory disorders and diseases.