NOD2 promotes sepsis-induced neuroinflammation by increasing brain endoplasmic reticulum stress mediated by LACC1

• Published in: Free radical biology & medicine Vol. 235; pp. 280 - 293
• Main Authors: Yi, Lingling, Chen, Zhuo, Zhou, Qiuping, Liu, Nan, Li, Qian, Wu, Xinghui, Zeng, Yu, Lin, Yiyan, Lin, Simin, Luo, Lifang, Jiang, Shuqi, Huang, Peixian, Wang, Huifang, Deng, Yiyu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2025
• Subjects: Animals; Brain - metabolism; Brain - pathology; Disease Models, Animal; Endoplasmic Reticulum Stress; Laccase domain-containing protein 1 (LACC1); Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Microglia - metabolism; Microglia - pathology; Neuroinflammatory Diseases - etiology; Neuroinflammatory Diseases - genetics; Neuroinflammatory Diseases - metabolism; Neuroinflammatory Diseases - pathology; Nod2 Signaling Adaptor Protein - genetics; Nod2 Signaling Adaptor Protein - metabolism; Nucleotide-binding oligomerization domain-containing protein 2 (NOD2); Phenylbutyrates - pharmacology; Sepsis - complications; Sepsis - genetics; Sepsis - metabolism; Sepsis - pathology; Sepsis-induced neuroinflammation; Sepsis-induced neuroinflammation; Nucleotide-binding oligomerization domain-containing protein 2 (NOD2); Laccase domain-containing protein 1 (LACC1); Endoplasmic reticulum stress; Microglia
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2025.05.002

Although nucleotide-binding oligomerization domain-containing protein 2 (NOD2) has been associated with diverse inflammatory states and some neurological diseases, its role in regulating sepsis-induced neuroinflammation remains unexplored. This study aimed to determine the role of NOD2 in modulating sepsis-induced neuroinflammation and to elucidate its potential mechanisms. mRNA and protein expression levels of NOD2 were measured in the periventricular white matter (PWM) of C57BL/6 mice and the microglia. NOD2−/− mice were generated using the CRISPR/Cas9 technology, and the septic mouse model was established by using cecal ligation puncture (CLP). Microglia were transfected with siRNA specific to NOD2 or laccase domain-containing protein 1 (LACC1) or treated with the endoplasmic reticulum stress (ER stress) inhibitor 4-phenylbutyrate (4-PBA) in vitro under muramyl dipeptide (MDP)-induced neuroinflammation. Immunofluorescence staining, Western blotting, and quantitative reverse transcription polymerase chain reaction were performed to evaluate neuroinflammation and ER stress. The ER structure was observed using transmission electron microscopy. NOD2 expression level was upregulated in the mouse model of sepsis-induced neuroinflammation. The absence of NOD2 led to a protective effect against neuroinflammation, which was correlated with ER stress both in vitro and in vivo. LACC1 was identified as a notable mediator of ER stress, contributing to the exacerbation of neuroinflammation. Mechanistically, elevated NOD2 expression level promoted neuroinflammation by enhancing ER stress through LACC1. Notably, these effects were partially mitigated by LACC1 downregulation. These findings highlight the pivotal role of NOD2 in promoting sepsis-induced neuroinflammation via regulating ER stress mediated by LACC1, and provide a new potential strategy for treating human neuroinflammation. NOD2 mediated sepsis-induced neuroinflammation through the LACC1-ER stress axis. A brief description of the illustration: In sepsis-induced neuroinflammation, NOD2 is activated in response to septic stimuli, leading to the upregulation of LACC1 in activated microglia. Increased LACC1 expression exacerbates endoplasmic reticulum (ER) stress in the brain, which in turn drives neuroinflammation. The administration of the ER stress inhibitor 4-PBA reduces the release of pro-inflammatory cytokines, thereby mitigating sepsis-induced neuroinflammation. It reveals a novel mechanism by which NOD2 contributes to sepsis-induced neuroinflammation. [Display omitted] •NOD2 expression is upregulated in sepsis-induced neuroinflammation.•NOD2 knockout alleviates neuroinflammation and ER stress.•NOD2 promotes neuroinflammation by enhancing ER stress.•The LACC1-ER stress axis acts as a pivotal mediator in NOD2-mediated neuroinflammation.