Pyroptotic Neuronal Cell Death Mediated by the AIM2 Inflammasome

Abstract

The central nervous system (CNS) is an active participant in the innate immune response to infection and injury. In these studies, we show embryonic cortical neurons express a functional, deoxyribonucleic acid (DNA)-responsive, absent in melanoma 2 (AIM2) inflammasome that activates caspase-1. Neurons undergo pyroptosis, a proinflammatory cell death mechanism characterized by the following: (a) oligomerization of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC); (b) caspase-1 dependency; (c) formation of discrete pores in the plasma membrane; and (d) release of the inflammatory cytokine interleukin-1b (IL-1b). Probenecid and Brilliant Blue FCF, inhibitors of the pannexin1 channel, prevent AIM2 inflammasome-mediated cell death, identifying pannexin1 as a cell death effector during pyroptosis and probenecid as a novel pyroptosis inhibitor. Furthermore, we show activation of the AIM2 inflammasome in neurons by cerebrospinal fluid (CSF) from traumatic brain injury (TBI) patients and oligomerization of ASC. These findings suggest neuronal pyroptosis is an important cell death mechanism during CNS infection and injury that may be attenuated by probenecid.

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

“…2,3 However, only few inflammasomes have been described and characterized in the CNS: The NLRP1 inflammasome in neurons, [4][5][6] the NLRP2 inflammasome in astrocytes, 7 the NLRP3 inflammasome in microglia, [8][9][10] and the absent in melanoma-2 (AIM2) inflammasome in neurons ( Figure 1). 11 However, other inflammasome sensors (including NLRP3, NLRP6, NLRP12, and interferon-g-inducible protein 16) may form inflammasomes in the CNS, but convincing data have not been generated to support this idea. Notable among the NLR sensors is NLRP3 that can be induced by amyloid-b through TLR activation and has been associated with the pathogenesis of Alzheimer's disease.…”

The Duality of AIM2 Inflammasome: A Focus on its Role in Autoimmunity and Skin Diseases

“…Adamczak and colleagues have demonstrated that human embryonal cortical neurons express functional AIM2 inflammasome, they release IL-1β and they undergo pyroptosis upon AIM2 activation with poly (dA:dT) transfection. Therefore, when exposed to the CSF of traumatic brain injury patients, they showed AIM2 upregulation and caspase-1 activation compared with embryonic cortical neurons that had been exposed to the CSF of non-trauma patients, indicating that CSF from injured patients is immunogenic and may cause pyropotosis in neighboring cells (Adamczak et al, 2014). These findings establish neuronal pyroptosis as a neuronal cell death mechanism, induced by activation of the AIM2 inflammasome (Adamczak et al, 2014).…”

“…For example, it has been shown that AIM2 is implicated in inflammation and cell death of the brain. Cerebrospinal Fluid (CSF) of patients with traumatic brain injury often contains cell-free DNA fragments rather than the CSF from non-trauma patients and this correlates with mortality (Adamczak et al, 2014;Campello Yurgel et al, 2007). Adamczak and colleagues have demonstrated that human embryonal cortical neurons express functional AIM2 inflammasome, they release IL-1β and they undergo pyroptosis upon AIM2 activation with poly (dA:dT) transfection.…”

“…Therefore, when exposed to the CSF of traumatic brain injury patients, they showed AIM2 upregulation and caspase-1 activation compared with embryonic cortical neurons that had been exposed to the CSF of non-trauma patients, indicating that CSF from injured patients is immunogenic and may cause pyropotosis in neighboring cells (Adamczak et al, 2014). These findings establish neuronal pyroptosis as a neuronal cell death mechanism, induced by activation of the AIM2 inflammasome (Adamczak et al, 2014). In the context of cancer, beyond its role in killing infected macrophages, pyroptosis may participate to the cellautonomous tumor suppression.…”

“…Whether the neutrophils release the vesicles, stored in the inflammasome compartments, into the extracellular microenvironments needs to be further elucidated (Bakele et al, 2014). Adamczak et al (2014) reported the presence of a functional AIM2-inflammasome in cortical neurons, which senses aberrant dsDNA through a mechanism leading to neural pyropotosis.…”