Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 May 30:13:863774.
doi: 10.3389/fimmu.2022.863774. eCollection 2022.

NLRP1 Inflammasomes: A Potential Target for the Treatment of Several Types of Brain Injury

Liang Mi  1   2 , Xiaobin Min  1   3 , Yan Chai  2 , Jianning Zhang  1   2 , Xin Chen  1   2
Affiliations
Review

NLRP1 Inflammasomes: A Potential Target for the Treatment of Several Types of Brain Injury

Liang Mi et al. Front Immunol. .

Abstract

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.

Keywords: NLRP1 inflammasome; neuroinflammation; stroke; subarachnoid hemorrhage; traumatic brain injury.

PubMed Disclaimer

Conflict of interest statement

The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Structures of NLRP1 inflammasome proteins. Unlike other NLRs, NLRP1 proteins have a FIIND and CARD at the C-terminus. The FIIND consists of ZU5 and UPA subdomains, and autoproteolysis takes place between them. In addition, NLRP1 proteins contain NACHT and LRR domains preceding the FIIND. Human NLRP1 also possesses a PYD domain at the N-terminus, which is absent in its rodent orthologs. ASC consists of a PYD and CARD, while pro-caspase-1 possesses a CARD before its catalytic p20 and p10 subunits.
Figure 2
Figure 2
Activation of the NLRP1 inflammasome. FIIND is autocleaved to activate NLRP1. Then, PYD undergoes cleavage, and the inflammasome complex subsequently forms, suggesting that PYD may play an autoinhibitory role. The binding of ASC can recruit pro-caspase-1. Then, pro-caspase-1 undergoes autocatalytic cleavage and forms the p10 and p20 subunits, which initiate the maturation and secretion of IL-1β and IL-18.
Figure 3
Figure 3
Direct activation of the NLRP1B inflammasome. NLRP1B undergoes autoproteolysis at the FIIND and generates the ZU5 and UPA subdomains. Then, LF cleavage between the K44 and L45 residues in the N-terminus produces an unstable N-terminal residue. The neo-N-terminus is subsequently recognized and ubiquitinated by the N-end rule E3 ligase UBR2, initiating proteasome-mediated degradation. The C-terminal fragment is free to recruit and stimulate pro-caspase-1.
Figure 4
Figure 4
The pathogen-associated effects induced by T. gondii infection, DPP8/9 inhibitors, or metabolic inhibitors can be detected by the indirect activation of the NLRP1 inflammasome. These activities can initiate perturbations in cells, which may stimulate the E3 ligase, resulting in the ubiquitination and degradation of the N-terminus of NLRP1.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Fan H, Ding R, Liu W, Zhang X, Li R, Wei B, et al. . Heat Shock Protein 22 Modulates NRF1/TFAM-Dependent Mitochondrial Biogenesis and DRP1-Sparked Mitochondrial Apoptosis Through AMPK-Pgc1α Signaling Pathway to Alleviate the Early Brain Injury of Subarachnoid Hemorrhage in Rats. Redox Biol (2021) 40:101856. doi: 10.1016/j.redox.2021.101856 - DOI - PMC - PubMed
    1. Macdonald RL, Schweizer TA. Spontaneous Subarachnoid Haemorrhage. Lancet (London England) (2017) 389:655–66. doi: 10.1016/S0140-6736(16)30668-7 - DOI - PubMed
    1. Chen J, Li M, Zhu X, Chen L, Yang S, Zhang C, et al. . Atorvastatin Reduces Cerebral Vasospasm and Infarction After Aneurysmal Subarachnoid Hemorrhage in Elderly Chinese Adults. Aging (2020) 12:2939–51. doi: 10.18632/aging.102788 - DOI - PMC - PubMed
    1. Chen J, Xuan Y, Chen Y, Wu T, Chen L, Guan H, et al. . Netrin-1 Alleviates Subarachnoid Haemorrhage-Induced Brain Injury via the Pparγ/NF-KB Signalling Pathway. J Cell Mol Med (2019) 23:2256–62. doi: 10.1111/jcmm.14105 - DOI - PMC - PubMed
    1. Chen JH, Wu T, Yang LK, Chen L, Zhu J, Li PP, et al. . Protective Effects of Atorvastatin on Cerebral Vessel Autoregulation in an Experimental Rabbit Model of Subarachnoid Hemorrhage. Mol Med Rep (2018) 17:1651–9. doi: 10.3892/mmr.2017.8074 - DOI - PMC - PubMed

Publication types

MeSH terms