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Background <p>Cognitive dysfunction is a prevalent mental health problem following hemorrhagic shock with resuscitation (HSR). Our previous work indicated that neuroinflammation caused by nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), which is modulated by glial cells, such as microglia, is potentially significant in developing emotional and cognitive dysfunction. However, little is known about the potential of microglial NLRP3 to treat HSR-induced cognitive dysfunction. Therefore, this study established an HSR rodent model to investigate whether microglial NLRP3 represents a potential therapeutic target for improving cognitive dysfunction after HSR.</p> Methods <p>An HSR model was developed by inducing bleeding and retransfusion in mice. The Morris water maze and Novel object recognition tests were used for behavioral evaluation. To selectively knock out the NLRP3 inflammasome in microglia, the AAV‑CX3CR1‑Cre (pAAV‑CX3CR1‑NLS‑Cre‑P2A‑EGFP‑3xFLAG‑WPRE) virus was stereotaxically injected into the hippocampal CA1 region of male C57BL/6 mice with NLRP3<sup>flox/flox</sup>. Immunofluorescence and local field potential recordings were used to assess pathological alterations at different intervals after injury.</p> Results <p>Our findings indicated that the NLRP3 inhibitor MCC950 significantly reversed HSR-induced lower recognition index, increased escape latency, reduced platform crossings, decreased θ and γ power and θ–γ phase coupling, decreased intensity of PSD95 and Synaptophysin, increased number of Iba1<sup>+</sup> cells, normalized soma size and total process length cell of Iba1, and increased colocalization of cleaved caspase-1 and interleukin-18 with Iba-1 in the CA1 area of the hippocampus. It also significantly alleviated the HSR-induced cognitive dysfunction. Moreover, we observed that HSR-induced cognitive dysfunction, neuroinflammation, and synaptic plasticity damage may be reversed by knocking out NLRP3 in the hippocampal CA1 microglia.</p> Conclusion <p>Our study demonstrates that inhibition of microglia‑specific NLRP3 can mitigate cognitive impairment following HSR, identifying microglial NLRP3 as a promising therapeutic target. This effect may be associated with suppressing pyroptosis via the NLRP3 signaling pathway in microglia.</p>

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Microglia-specific NLRP3 inhibition mitigates hippocampal neuroinflammation and cognitive deficits after hemorrhagic shock with resuscitation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Ya-Mei Zhang,
  • Meng-Yue Wang,
  • Zhong-Yong Zhang,
  • Xin-Yu Yang,
  • Hong-Lian Duan,
  • Jian-Kai Sun,
  • Xiao-Yi Ma,
  • Rong-Xin Song,
  • Jing-Yu Hui,
  • Dong-Xue Zhang,
  • Li-Min Zhang,
  • Hui-Tao Miao

摘要

Background

Cognitive dysfunction is a prevalent mental health problem following hemorrhagic shock with resuscitation (HSR). Our previous work indicated that neuroinflammation caused by nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), which is modulated by glial cells, such as microglia, is potentially significant in developing emotional and cognitive dysfunction. However, little is known about the potential of microglial NLRP3 to treat HSR-induced cognitive dysfunction. Therefore, this study established an HSR rodent model to investigate whether microglial NLRP3 represents a potential therapeutic target for improving cognitive dysfunction after HSR.

Methods

An HSR model was developed by inducing bleeding and retransfusion in mice. The Morris water maze and Novel object recognition tests were used for behavioral evaluation. To selectively knock out the NLRP3 inflammasome in microglia, the AAV‑CX3CR1‑Cre (pAAV‑CX3CR1‑NLS‑Cre‑P2A‑EGFP‑3xFLAG‑WPRE) virus was stereotaxically injected into the hippocampal CA1 region of male C57BL/6 mice with NLRP3flox/flox. Immunofluorescence and local field potential recordings were used to assess pathological alterations at different intervals after injury.

Results

Our findings indicated that the NLRP3 inhibitor MCC950 significantly reversed HSR-induced lower recognition index, increased escape latency, reduced platform crossings, decreased θ and γ power and θ–γ phase coupling, decreased intensity of PSD95 and Synaptophysin, increased number of Iba1+ cells, normalized soma size and total process length cell of Iba1, and increased colocalization of cleaved caspase-1 and interleukin-18 with Iba-1 in the CA1 area of the hippocampus. It also significantly alleviated the HSR-induced cognitive dysfunction. Moreover, we observed that HSR-induced cognitive dysfunction, neuroinflammation, and synaptic plasticity damage may be reversed by knocking out NLRP3 in the hippocampal CA1 microglia.

Conclusion

Our study demonstrates that inhibition of microglia‑specific NLRP3 can mitigate cognitive impairment following HSR, identifying microglial NLRP3 as a promising therapeutic target. This effect may be associated with suppressing pyroptosis via the NLRP3 signaling pathway in microglia.