Role of NLRP3 inflammasome activation in the pyroptotic cell death of glial cells

Abstract

Inflammasome is a caspase-1-activating multi-protein complex composed of sensor molecules such as NOD-like receptor family, pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and procaspase-1. The inflammasome complex plays a crucial role in the induction of inflammatory responses mainly in myeloid cells such as macrophages. Assembly of the inflammasome complex induces the activation of caspase-1, which leads to the maturation and release of pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18. Also, active caspase-1 cleaves gasdermin D (GSDMD) which initiates generation of pores in plasma membrane and leads to ‘pyroptosis’, a form of programmed lytic cell death. Recent studies have proposed that NLRP3 inflammasome possibly contribute to neuroinflammation and neurodegenerative diseases. Also, NLRP3 inflammasome complexes are activated in glial cells and glial inflammasome activation is critical to various neurologic disorders. However, the effects of glial pyroptosis in neuroinflammation are still poorly understood. Here, I examined the effect of mixed glial pyroptosis upon NLRP3 inflammasome activation. Active caspase-1 and IL-1β was secreted by lipopolysaccharide (LPS) and ATP stimulation in mixed glia. However, pyroptosis of mixed glia with LPS plus ATP treatment were reduced, not like bone marrow-derived macrophages (BMDMs). Furthermore, attenuated pyroptosis of mixed glia was not related to GSDMD, the effector of pyroptosis. Next, microglia were isolated from mixed glia and examined NLRP3 inflammasome-mediated pyroptosis. Interestingly, pyroptosis of microglia present in mixed glia showed a weaker response than pyroptosis of isolated microglia. Additionally, mixed glia showed less toxicity to SH-SY5Y, dopaminergic neuroblastoma cell line, than BMDMs upon LPS/ATP stimulation with coculture system. Collectively, mixed glia showed NLRP3 inflammasome-mediated attenuated pyroptosis than BMDMs and interaction between glial cells potentially reduced microglial pyroptosis.