2. Academic Validation
  3. Targeting RelA/NLRP3/CCL3 axis mitigates microglia inflammatory response and promotes recovery after spinal cord injury

Targeting RelA/NLRP3/CCL3 axis mitigates microglia inflammatory response and promotes recovery after spinal cord injury

  • Brain Behav Immun. 2025 Oct:129:801-817. doi: 10.1016/j.bbi.2025.07.015.
Wei Song 1,  Runhan Fu 1,  Zhongze Yuan 2,  Yanchun Liu 1,  Yanbing Kao 1,  Renjie Zhang 2,  Guangjin Gu 1,  Hanming Zhu 2,  Haoyun Liu 1,  Zhihao Zhang 1,  Xiaohong Kong 3,  Shiqing Feng 4
Affiliations

Affiliations

  • 1 Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong, China; Orthopedic Research Center of Shandong University &Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 2 Department of Orthopedics, Second Hospital of Shandong University, Jinan, Shandong, China; Orthopedic Research Center of Shandong University &Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 3 Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong, China; Orthopedic Research Center of Shandong University &Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. Electronic address: kongxh@sdu.edu.cn.
  • 4 Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong, China; Department of Orthopedics, Second Hospital of Shandong University, Jinan, Shandong, China; Orthopedic Research Center of Shandong University &Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. Electronic address: shiqingfeng@sdu.edu.cn.
PMID: 40691997 DOI: 10.1016/j.bbi.2025.07.015
Abstract

Spinal cord injury (SCI) leads to loss of motor and sensory function below the lesion site, presenting a lifelong burden of disability. During the acute phase of SCI, microglia develop an inflammatory phenotype, characterized by the NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling activation, exacerbating tissue damage and impeding trauma recovery. However, the molecular mechanisms underlying this process remain unclear. Here we show that conditional knockout of NLRP3 in microglia using NLRP3fl/fl; Cx3cr1-CreERT; Rosa26-tdTomato mice (Nlrp3ΔMG) confers neuroprotection by preserving neuron survival and mitigating tissue damage during the acute phase of SCI. Mechanistically, NLRP3 ablation in microglia attenuates the activation of pyroptosis-related signaling pathways in microglia and suppresses the production of inflammatory cytokines (IL-1β, IL-18, CCL3, and CCL5). Furthermore, we identify RelA as a transcriptional regulator of NLRP3, binding to its promoter and upregulating its expression in activated microglia. Inhibition of RelA using pyrrolidine dithiocarbamate ammonium (PDTC), a blood-brain barrier permeable drug, effectively downregulates NLRP3 expression and suppresses spinal cord inflammation, thereby contributing to neuroprotection. Our findings demonstrate the crucial role of RelA/NLRP3/CCL3 axis in modulating microglial inflammation and highlight its potential as a therapeutic target to promote recovery post SCI.

Keywords

CCL3; Inflammatory response; Microglia; NLRP3; RelA; Spinal cord injury.

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