Critical role for the AIM2 inflammasome during acute CNS bacterial infection

Abstract

Interleukin-1β (IL-1β) is essential for eliciting protective immunity during the acute phase of Staphylococcus aureus (S. aureus) infection in the central nervous system (CNS). We previously demonstrated that microglial IL-1β production in response to live S. aureus is mediated through the Nod-like receptor protein 3 (NLRP3) inflammasome, including the adapter protein ASC (apoptosis-associated, speck-like, caspase-1 recruiting domain-containing protein), and pro-caspase-1. Here we utilized NLRP3, ASC, and caspase-1/11 knockout (KO) mice to demonstrate the functional significance of inflammasome activity during CNS S. aureus infection. ASC and caspase-1/11 KO animals were exquisitely sensitive, with approximately 50% of mice succumbing to infection within 24 h. Unexpectedly, the survival of NLRP3 KO mice was similar to WT animals, suggesting the involvement of an alternative upstream sensor, which was later identified as absent in melanoma 2 (AIM2) based on the similar disease patterns between AIM2 and ASC KO mice. Besides IL-1β, other key inflammatory mediators, including IL-6, CXCL1, CXCL10, and CCL2 were significantly reduced in the CNS of AIM2 and ASC KO mice, implicating autocrine/paracrine actions of IL-1β, since these mediators do not require inflammasome processing for secretion. These studies demonstrate a novel role for the AIM2 inflammasome as a critical molecular platform for regulating IL-1β release and survival during acute CNS S. aureus infection.

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

“…Cultured embryonic rat cortical neurons undergo an AIM2-inflammasome-dependent cell death when challenged with the AIM2 activator poly(dA:dT) (12). AIM2 inflammasomes also drive a protective inflammatory response in the brain, and AIM2 −/− mice show reduced survival in response to central infection with Staphylococcus aureus (43). This latter study also shows a disconnect between NLRP3 and ASC because ASC −/− mice are also more susceptible to central S. aureus infection, whereas the survival of NLRP3 −/− mice is comparable to WT (43).…”

“…AIM2 inflammasomes also drive a protective inflammatory response in the brain, and AIM2 −/− mice show reduced survival in response to central infection with Staphylococcus aureus (43). This latter study also shows a disconnect between NLRP3 and ASC because ASC −/− mice are also more susceptible to central S. aureus infection, whereas the survival of NLRP3 −/− mice is comparable to WT (43). These observations, together with our data, suggest that AIM2 is an important sensor of infection and injury in the brain in vivo.…”

Emerging Roles for the Immune System in Traumatic Brain Injury

“…Since the finding that inflammasome proteins are upregulated after TBI in human patients (98), significant attention has been paid to identify the inflammasome-associated signaling events that are engaged in response to brain trauma (14, 99, 100). Inflammasome literature has identified the expression of NLRP1, NLRP2, and NLRP3 as well as AIM2 inflammasomes in microglia, neurons, and astrocytes in the CNS (100–104).…”

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 2)

“…Протеин NLRC5 связывается с NLRP3 и усиливает секрецию цитокинов; NLRP7, связываясь с АТФ, способству-ет активации каспазы-1 в ответ на инфицирование Staphylococcus aureus [15,20,39,72,85]. Активация AIM2-инфламмасомы в иммуноцитах при стафило-кокковой инфекции происходит преимущественно при поражении центральной нервной системы [31].…”