Activation and regulation of cellular inflammasomes: gaps in our knowledge for central nervous system injury

Abstract

The inflammasome is an intracellular multiprotein complex involved in the activation of caspase-1 and the processing of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. The inflammasome in the central nervous system (CNS) is involved in the generation of an innate immune inflammatory response through IL-1 cytokine release and in cell death through the process of pyroptosis. In this review, we consider the different types of inflammasomes (NLRP1, NLRP2, NLRP3, and AIM2) that have been described in CNS cells, namely neurons, astrocytes, and microglia. Importantly, we focus on the role of the inflammasome after brain and spinal cord injury and cover the potential activators of the inflammasome after CNS injury such as adenosine triphosphate and DNA, and the therapeutic potential of targeting the inflammasome to improve outcomes after CNS trauma.

Figure 1

Inflammasome structure. The sensory component of NOD-like receptors (NLRs) or AIM2-like receptors interacts with the adaptor protein ASC and caspase-1. (A) The NLRP1 inflammasome in neurons differs from that in macrophages in that it also contains X-linked inhibitor of apoptosis protein (XIAP) and caspase-11. (B) The NLRP2 inflammasome is present in astrocytes and comprises caspase-1, ASC, and NLRP2. (C) In microglia, the NLRP3 inflammasome comprises NLRP3, ASC, and caspase-1, whereas (D) in neurons the AIM2 inflammasome comprises caspase-1, ASC, and AIM2.

Figure 2

Mechanism of inflammasome activation involving P2X4, P2X7, and the pannexin-1 channel. (1.1) In the uninjured central nervous system (CNS), the neuronal NLRP1 inflammasome is a multiprotein complex consisting of inflammatory caspase-1, caspase-11, NLRP1, the adaptor protein ASC, and the inhibitor of apoptosis protein X-linked inhibitor of apoptosis protein (XIAP) that are linked to P2X7 and pannexin-1. (1.2) Danger/damage-associated molecular patterns (DAMPs) activate distinct toll-like receptors (TLRs), which initiate a complex sequence of signaling events leading to synthesis of pro-IL-1β. This step is referred to as priming. (2) Upon inflammasome activation, XIAP is cleaved, thus decreasing its inhibitory capacity on caspase-1. (3) Adenosine triphosphate (ATP) released from dying cells activates P2X4. (4) P2X4 then facilitates K+ efflux, resulting in opening of the pannexin-1 channels. High extracellular potassium opens the pannexin-1 channel that results in ATP release. Adenosine triphosphate released from pannexin-1 further increases the extracellular levels of ATP. (5) High extracellular levels of ATP activate P2X7. (6) Upon inflammasome activation, pro-IL-1β and pro-IL-18 are cleaved into their respective active forms, IL-1β and IL-18. (7) Mature (bioactive) IL-1β and IL-18 are secreted into the extracellular space by an unknown release mechanism. Panx-1, pannexin-1.

Figure 3

Activators and inhibitors of the inflammasome. Inflammasomes are activated by danger-associated molecular patterns (DAMPS) that result in caspase-1 activation and processing of the proinflammatory cytokines IL-1β and IL-18. Resolution of inflammation results in tissue homeostasis, but chronic inflammatory response may result in cell death. Inhibitors of the inflammasome are grouped endogenous such as ICEBERG, INCA, or POP or exogenous such as probenecid, carbenoxolone, glyburide, or YVAD. MSU, monosodium urate; UV, ultraviolet.

Figure 4

Unsolved problems in inflammasome regulation in the central nervous system (CNS). How are pannexin-1, P2X4, and P2X7 are involved in inflammasome activation through potassium and ATP? Does calcium have a role on inflammasome activation in the CNS? Does β-amyloid activate other inflammasomes in addition to NLRP3? How does reactive oxygen species (ROS) have a role in inflammasome activation? What is the role of mitochondria in inflammasome activation? How does the inflammasome activation lead to pyroptosis? Are there additional activators and inhibitors of inflammasomes? Do protein modifications such as phosphorylation or ubiquitination have a role on regulating activation of the inflammasome? How much inflammasome activation is beneficial and when does it become detrimental?