Brain injury is the leading cause of death and disability in survivors of cardiac arrest,where neuroinflammation triggered by infiltrating macrophages plays a pivotal role.Here,we seek to elucidate the origin of macro...Brain injury is the leading cause of death and disability in survivors of cardiac arrest,where neuroinflammation triggered by infiltrating macrophages plays a pivotal role.Here,we seek to elucidate the origin of macrophages infiltrating the brain and their mechanism of action after cardiac arrest/cardiopulmonary resuscitation(CA/CPR).Wild-type or photoconvertible Cd68-Cre:R26-LSL-KikGR mice were subjected to 10-min CA/CPR,and the migration of gut-derived macrophages into brain was assessed.Transcriptome sequencing was performed to identify the key proinflammatory signal of macrophages infiltrating the brain,triggering receptor expressed on myeloid cells 1(TREM1).Upon drug intervention,the effects of TREM1 on post-CA/CPR brain injury were further evaluated.16S rRNA sequencing was used to detect gut dysbiosis after CA/CPR.Through photoconversion experiments,we found that small intestine-derived macrophages infiltrated the brain and played a crucial role in triggering secondary brain injury after CA/CPR.The infiltrating peripheral macrophages showed upregulated TREM1 levels,and we further revealed the crucial role of gut-derived TREM1+macrophages in post-CA/CPR brain injury through a drug intervention targeting TREM1.Moreover,a close correlation between upregulated TREM1 expression and poor neurological outcomes was observed in CA survivors.Mechanistically,CA/CPR caused a substantial expansion of Enterobacter at the early stage,which ignited intestinal TREM1 signaling via the activation of Toll-like receptor 4 on macrophages through the release of lipopolysaccharide.Our findings reveal essential crosstalk between the gut and brain after CA/CPR and underscore the potential of targeting TREM1+small intestine-derived macrophages as a novel therapeutic strategy for mitigating post-CA/CPR brain injury.展开更多
基金supported by the National Natural Science Foundation of China(82072133&82371467&82171345)Jiangxi Provincial Natural Science Foundation(20232ACB216008)+4 种基金Guangzhou Science and Technology Planning Project(202206010032)Guangdong Basic and Applied Basic Research Foundation(2023A1515110506&2021A1515010922)the China Postdoctoral Science Foundation(2024M751319)the Postdoctoral Fellowship Program of CPSF(GZC20231066)the President Foundation of Nanfang Hospital,Southern Medical University(2023A005).
文摘Brain injury is the leading cause of death and disability in survivors of cardiac arrest,where neuroinflammation triggered by infiltrating macrophages plays a pivotal role.Here,we seek to elucidate the origin of macrophages infiltrating the brain and their mechanism of action after cardiac arrest/cardiopulmonary resuscitation(CA/CPR).Wild-type or photoconvertible Cd68-Cre:R26-LSL-KikGR mice were subjected to 10-min CA/CPR,and the migration of gut-derived macrophages into brain was assessed.Transcriptome sequencing was performed to identify the key proinflammatory signal of macrophages infiltrating the brain,triggering receptor expressed on myeloid cells 1(TREM1).Upon drug intervention,the effects of TREM1 on post-CA/CPR brain injury were further evaluated.16S rRNA sequencing was used to detect gut dysbiosis after CA/CPR.Through photoconversion experiments,we found that small intestine-derived macrophages infiltrated the brain and played a crucial role in triggering secondary brain injury after CA/CPR.The infiltrating peripheral macrophages showed upregulated TREM1 levels,and we further revealed the crucial role of gut-derived TREM1+macrophages in post-CA/CPR brain injury through a drug intervention targeting TREM1.Moreover,a close correlation between upregulated TREM1 expression and poor neurological outcomes was observed in CA survivors.Mechanistically,CA/CPR caused a substantial expansion of Enterobacter at the early stage,which ignited intestinal TREM1 signaling via the activation of Toll-like receptor 4 on macrophages through the release of lipopolysaccharide.Our findings reveal essential crosstalk between the gut and brain after CA/CPR and underscore the potential of targeting TREM1+small intestine-derived macrophages as a novel therapeutic strategy for mitigating post-CA/CPR brain injury.
