TGM2 Enhances Hypobaric Hypoxia-mediated Brain Injury Via Regulating NLRP3/GSDMD Signaling

High-altitude hypoxic brain injury (HHBI) is characterized by neuronal damage. Transglutaminase 2 (TGM2) promotes neuroinflammation and the progression of various brain diseases. This study aimed to investigate the role of TGM2. In vivo HHBI models were established using an animal HH chamber. In vitro HHBI models were established using oxygen-glucose deprivation (OGD). Cytokine release was detected using enzyme-linked immunosorbent assay (ELISA). Protein expression was detected using was detected using western blot. NeuN and IBA1 was expression was detected using immunofluorescence. The co-localization of NLR family pyrin domain containing 3 (NLRP3) was analyzed by fluorescent in situ hybridization (FISH) assay. NLRP3 and TGM2 The interaction between TGM2 and NLRP3 inflammasome was verified using Co-immunoprecipitation (Co-IP) assay. Cytotoxicity of neurons was detected using lactate dehydrogenase (LDH) assay. Neuronal viability was detected using cell counting kit-8 (CCK-8) assay. Neuronal death was determined using terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay. We found that HH exposure promoted neuronal inflammation and death, contributing to cognitive impairment in vivo. Moreover, HHBI mediated the upregulation of TGM2. However, TGM2 knockdown significantly restored neuronal functions, manifested by suppressing neuronal inflammation and pyroptosis. TGM2 bound to NLRP3 inflammasome, which precipitated endogenous gasdermin D (GSDMD-N) and promoted the expression of N-terminal of GSDMD (GSDMD-N). However, overexpression of NLRP3 abated the effects of TGM2 and promoted neuroinflammation and neuronal pyroptosis. Conclusions: TGM2 promoted neuronal pyroptosis in HHBI via activating NLRP3/GSDMD signaling, contributing to cognitive impairment. Therefore, targeting TGM2/NLRP3 signaling provide a novel strategy for HHBI.