Biliverdin reductase-A attenuated GMH-induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS/NO pathway
Abstract Background Germinal matrix hemorrhage (GMH) is a common neurologic event with high morbidity and mortality in preterm infants. Spleen has been reported to play a critical role in inflammatory responses by regulating peripheral immune cells which contributes to secondary brain injury. Method...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2018-04-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-018-1155-z |
| _version_ | 1811226873878806528 |
|---|---|
| author | Yiting Zhang Yan Ding Tai Lu Yixin Zhang Ningbo Xu Devin W. McBride Jiping Tang John H. Zhang |
| author_facet | Yiting Zhang Yan Ding Tai Lu Yixin Zhang Ningbo Xu Devin W. McBride Jiping Tang John H. Zhang |
| author_sort | Yiting Zhang |
| collection | DOAJ |
| description | Abstract Background Germinal matrix hemorrhage (GMH) is a common neurologic event with high morbidity and mortality in preterm infants. Spleen has been reported to play a critical role in inflammatory responses by regulating peripheral immune cells which contributes to secondary brain injury. Methods The current study investigated the mechanistic role of biliverdin reductase-A (BLVRA) in the splenic response and brain damage in neonates following a collagenase GMH model. Neurological outcomes and splenic weights were assessed. Neutrophil production and infiltration were quantitated in the spleen and brain, respectively. Western blot was performed in both splenic and brain tissues to measure protein levels of toll-like receptor 4 and proinflammatory cytokines. Results BLVRA treatment alleviated GMH-induced developmental delay and attenuated splenic atrophy at 1 and 3 days after GMH. Quantification analysis showed that spleen-stored peripheral immune cells mobilized into circulation and infiltrated in the brain following GMH, which was abrogated by BLVRA administration, resulting in reduced splenic inflammatory response. Furthermore, we showed that regulation of eNOS/NO signaling by BLVRA stimulation blunted toll-like receptor-4 (TLR4) signal. The eNOS-generated NO, in part, translocated BLVRA into the nucleus, where BLVRA inhibited TLR4 expression. Conclusion We revealed a BLVRA-dependent signaling pathway in modulating the splenic inflammation in response to GMH via the eNOS/NO/TLR4 pathway. |
| first_indexed | 2024-04-12T09:32:09Z |
| format | Article |
| id | doaj.art-33392782b88f4c39837857424cef9015 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-12T09:32:09Z |
| publishDate | 2018-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-33392782b88f4c39837857424cef90152022-12-22T03:38:19ZengBMCJournal of Neuroinflammation1742-20942018-04-0115111210.1186/s12974-018-1155-zBiliverdin reductase-A attenuated GMH-induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS/NO pathwayYiting Zhang0Yan Ding1Tai Lu2Yixin Zhang3Ningbo Xu4Devin W. McBride5Jiping Tang6John H. Zhang7Department of Ophthalmology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Physiology and Pharmacology, Loma Linda University School of MedicineDepartment of Physiology and Pharmacology, Loma Linda University School of MedicineDepartment of Physiology and Pharmacology, Loma Linda University School of MedicineDepartment of Physiology and Pharmacology, Loma Linda University School of MedicineDepartment of Physiology and Pharmacology, Loma Linda University School of MedicineDepartment of Physiology and Pharmacology, Loma Linda University School of MedicineDepartment of Physiology and Pharmacology, Loma Linda University School of MedicineAbstract Background Germinal matrix hemorrhage (GMH) is a common neurologic event with high morbidity and mortality in preterm infants. Spleen has been reported to play a critical role in inflammatory responses by regulating peripheral immune cells which contributes to secondary brain injury. Methods The current study investigated the mechanistic role of biliverdin reductase-A (BLVRA) in the splenic response and brain damage in neonates following a collagenase GMH model. Neurological outcomes and splenic weights were assessed. Neutrophil production and infiltration were quantitated in the spleen and brain, respectively. Western blot was performed in both splenic and brain tissues to measure protein levels of toll-like receptor 4 and proinflammatory cytokines. Results BLVRA treatment alleviated GMH-induced developmental delay and attenuated splenic atrophy at 1 and 3 days after GMH. Quantification analysis showed that spleen-stored peripheral immune cells mobilized into circulation and infiltrated in the brain following GMH, which was abrogated by BLVRA administration, resulting in reduced splenic inflammatory response. Furthermore, we showed that regulation of eNOS/NO signaling by BLVRA stimulation blunted toll-like receptor-4 (TLR4) signal. The eNOS-generated NO, in part, translocated BLVRA into the nucleus, where BLVRA inhibited TLR4 expression. Conclusion We revealed a BLVRA-dependent signaling pathway in modulating the splenic inflammation in response to GMH via the eNOS/NO/TLR4 pathway.http://link.springer.com/article/10.1186/s12974-018-1155-zGerminal matrix hemorrhageBiliverdin reductase-AToll-like receptor 4Splenic responseEndothelial nitric oxide synthase |
| spellingShingle | Yiting Zhang Yan Ding Tai Lu Yixin Zhang Ningbo Xu Devin W. McBride Jiping Tang John H. Zhang Biliverdin reductase-A attenuated GMH-induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS/NO pathway Journal of Neuroinflammation Germinal matrix hemorrhage Biliverdin reductase-A Toll-like receptor 4 Splenic response Endothelial nitric oxide synthase |
| title | Biliverdin reductase-A attenuated GMH-induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS/NO pathway |
| title_full | Biliverdin reductase-A attenuated GMH-induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS/NO pathway |
| title_fullStr | Biliverdin reductase-A attenuated GMH-induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS/NO pathway |
| title_full_unstemmed | Biliverdin reductase-A attenuated GMH-induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS/NO pathway |
| title_short | Biliverdin reductase-A attenuated GMH-induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS/NO pathway |
| title_sort | biliverdin reductase a attenuated gmh induced inflammatory response in the spleen by inhibiting toll like receptor 4 through enos no pathway |
| topic | Germinal matrix hemorrhage Biliverdin reductase-A Toll-like receptor 4 Splenic response Endothelial nitric oxide synthase |
| url | http://link.springer.com/article/10.1186/s12974-018-1155-z |
| work_keys_str_mv | AT yitingzhang biliverdinreductaseaattenuatedgmhinducedinflammatoryresponseinthespleenbyinhibitingtolllikereceptor4throughenosnopathway AT yanding biliverdinreductaseaattenuatedgmhinducedinflammatoryresponseinthespleenbyinhibitingtolllikereceptor4throughenosnopathway AT tailu biliverdinreductaseaattenuatedgmhinducedinflammatoryresponseinthespleenbyinhibitingtolllikereceptor4throughenosnopathway AT yixinzhang biliverdinreductaseaattenuatedgmhinducedinflammatoryresponseinthespleenbyinhibitingtolllikereceptor4throughenosnopathway AT ningboxu biliverdinreductaseaattenuatedgmhinducedinflammatoryresponseinthespleenbyinhibitingtolllikereceptor4throughenosnopathway AT devinwmcbride biliverdinreductaseaattenuatedgmhinducedinflammatoryresponseinthespleenbyinhibitingtolllikereceptor4throughenosnopathway AT jipingtang biliverdinreductaseaattenuatedgmhinducedinflammatoryresponseinthespleenbyinhibitingtolllikereceptor4throughenosnopathway AT johnhzhang biliverdinreductaseaattenuatedgmhinducedinflammatoryresponseinthespleenbyinhibitingtolllikereceptor4throughenosnopathway |