Inflammasomes in the CNS

Abstract

Microglia and macrophages in the CNS contain multimolecular complexes termed inflammasomes. Inflammasomes function as intracellular sensors for infectious agents as well as for host-derived danger signals that are associated with neurological diseases, including meningitis, stroke and Alzheimer's disease. Assembly of an inflammasome activates caspase 1 and, subsequently, the proteolysis and release of the cytokines interleukin-1β and interleukin-18, as well as pyroptotic cell death. Since the discovery of inflammasomes in 2002, there has been burgeoning recognition of their complexities and functions. Here, we review the current understanding of the functions of different inflammasomes in the CNS and their roles in neurological diseases.

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

“…Microglia and astrocytes have received considerable attention recently due to their contributions to a wide array of homeostatic and non-inflammatory processes, as well as during states of heightened inflammation and injury (Brown and Neher, 2014;Ginhoux and Jung, 2014;Prinz and Priller, 2014;Salter and Beggs, 2014;Walsh et al, 2014). Glial and neuroimmune mechanisms have been extensively characterized in the context of pathological pain (Grace et al, 2014a), while researchers attempting to decode the complex etiology of neurodegenerative disorders such as Alzheimer's disease have also argued for a more holistic framework, where the interactions and compensatory responses between neurons, glia, and vascular cells all contribute to the progression of the disease (De Strooper and Karran, 2016).…”

Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders

“…It should be noted that microglia express PPRs such as TLRs, which include TLR2 and TLR4, and TLR ligation potently activates microglia (Aravalli et al, 2007). In addition, several inflammasomes have been characterized in microglia including NLRP1, NLRP3, and NLRC4 (Walsh et al, 2014). Notably, several studies have characterized inflammasomes in neurons Kummer et al, 2007), which are capable of producing IL-1β (de Rivero Vaccari et al, 2009).…”

“…Notably, several studies have characterized inflammasomes in neurons Kummer et al, 2007), which are capable of producing IL-1β (de Rivero Vaccari et al, 2009). The NLRP3 inflammasome has been the most studied inflammasome in the CNS (Walsh et al, 2014), and as expanded upon below, has also been the focus of the preponderance of studies into the role of inflammasomes in animal models of depression. Interestingly, recent investigations into the effects of stress on NLRP3 in the CNS suggest that NLRP3 may also be uniquely sensitive to the homeostatic perturbations produced by stress.…”

“…Inflammasomes are intracellular multiprotein complexes that function as sensors of DAMPs or PAMPs, which leads to the activation of proinflammatory caspases, and the cleavage and release of proinflammatory cytokines (Walsh et al, 2014). Several distinct inflammasomes have been characterized, which generally consist of a cytosolic sensor (eg, a nucleotide binding domain), an adaptor protein (eg, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)), and an effector caspase, typically caspase-1.…”

Innate immune responses regulate morphogenesis and degeneration: roles of Toll-like receptors and Sarm1 in neurons

“…At the protein level, only IL-6 and TNFα are detectable in the culture supernatant [11] . Because IL-1β requires a second signal to activate the infl ammasome and caspase 1 to cleave pro-IL-1β to IL-1β [35,36] , the undetectable level of IL-1β in the supernatant is likely due to the lack of a second stimulus to activate the infl ammasome. Between IL-6 and TNFα, only IL-6 is critical for restricting the dendritic outgrowth of cultured neurons because IL-6 knockout neurons lose their response to TLR7 activation [11] .…”