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NOD-like receptor (NLR) family pyrin domain-containing 1 (NLRP1) is a member of the NLR family. The NLRP1 inflammasome consists of the NLRP1 protein, the adaptor protein apoptosis-associated speck-like protein containing a CARD domain, and the effector molecule pro-caspase-1. When stimulated, the inflammasome initiates the cleavage of pro-caspase-1 and converts it into its active form, caspase-1; then, caspase-1 facilitates the cleavage of the proinflammatory cytokines interleukin-1β and interleukin-18 into their active and secreted forms. In addition, caspase-1 also mediates the cleavage of gasdermin D, which leads to pyroptosis, an inflammatory form of cell death. Pathological events that damage the brain and result in neuropathological conditions can generally be described as brain injury. Neuroinflammation, especially that driven by NLRP1, plays a considerable role in the pathophysiology of brain injury, such as early brain injury (EBI) of subarachnoid hemorrhage, ischemic brain injury during stroke, and traumatic brain injury (TBI). In this article, a thorough overview of NLRP1 is presented, including its structure, mechanism of activation, and role in neuroinflammation. We also present recent studies on NLRP1 as a target for the treatment of EBI, ischemic brain injury, TBI, and other types of brain injury, thus highlighting the perspective of NLRP1 as an effective mediator of catastrophic brain injury.

Background: Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) is associated with neuroinflammation and subsequent cell death following traumatic brain injury (TBI). The sigma-1 receptor (Sig-1R) acts as a dynamic pluripotent modulator of fundamental cellular processes at the mitochondria-associated membranes (MAMs). The activation of Sig-1R is neuroprotective in a variety of central nervous system diseases, but its impact on ER stress induced by traumatic brain injury is not known. This study investigated the role of Sig-1R in regulating the ER stress-mediated microglial activation and programmed cell death (apoptosis and pyroptosis) induced by TBI. Methods: Ten human brain tissues were obtained from The Tianjin Medical University General Hospital. Four normal brain tissues were obtained from patients who underwent surgery for cerebral vascular malformation, through which peripheral brain tissues were isolated. Six severe TBI tissues were from patients with brain injury caused by accidents. None of the patients had any other known neurological disorders. Mice with Sig-1R deletion using CRISPR technology were subjected to controlled cortical impact-induced injury. In parallel, wild type C57BL/6J mice were analyzed for outcomes after they were exposed to TBI and received the Sig-1R agonist PRE-084 (10 mg/kg daily for three days) either alone or in combination with the Sig-1R antagonist BD-1047 (10 mg/kg). Results: The expression of Sig-1R and the 78 kDa glucose-regulated protein, a known UPR marker, were significantly elevated in the injured cerebral tissues from TBI patients and mice subjected to TBI. PRE-084 improved neurological function, restored the cerebral cortical perfusion, and ameliorated and brain edema in C57BL/6J mice subjected to TBI by reducing endoplasmic reticulum stress-mediated apoptosis, pyroptosis, and microglia activation. The effect of PRE-084 was abolished in mice receiving Sig-1R antagonist BD-1047. Conclusions: ER stress and UPR were upregulated in TBI patients and mice subjected to TBI. Sig-1R activation by the exogenous activator PRE-084 attenuated microglial cells activation, reduced ER stress-associated programmed cell death, and restored cerebrovascular and neurological function in TBI mice.

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