Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2
Abstract Background Diabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. However, the precise role of TonEB...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-11-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-021-02331-8 |
| _version_ | 1819202868572323840 |
|---|---|
| author | Eun Ae Jeong Jaewoong Lee Hyun Joo Shin Jong Youl Lee Kyung Eun Kim Hyeong Seok An Deok Ryong Kim Kyu Yeong Choi Kun Ho Lee Gu Seob Roh |
| author_facet | Eun Ae Jeong Jaewoong Lee Hyun Joo Shin Jong Youl Lee Kyung Eun Kim Hyeong Seok An Deok Ryong Kim Kyu Yeong Choi Kun Ho Lee Gu Seob Roh |
| author_sort | Eun Ae Jeong |
| collection | DOAJ |
| description | Abstract Background Diabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. However, the precise role of TonEBP in the diabetic brain is not fully understood. Methods We employed a high-fat diet (HFD)-only fed mice or HFD/streptozotocin (STZ)-treated mice in our diabetic mouse models. Circulating TonEBP and lipocalin-2 (LCN2) levels were measured in type 2 diabetic subjects. TonEBP haploinsufficient mice were used to investigate the role of TonEBP in HFD/STZ-induced diabetic mice. In addition, RAW 264.7 macrophages were given a lipopolysaccharide (LPS)/high glucose (HG) treatment. Using a siRNA, we examined the effects of TonEBP knockdown on RAW264 cell’ medium/HG-treated mouse hippocampal HT22 cells. Results Circulating TonEBP and LCN2 levels were higher in experimental diabetic mice or type 2 diabetic patients with cognitive impairment. TonEBP haploinsufficiency ameliorated the diabetic phenotypes including adipose tissue macrophage infiltrations, neuroinflammation, blood–brain barrier leakage, and memory deficits. Systemic and hippocampal LCN2 proteins were reduced in diabetic mice by TonEBP haploinsufficiency. TonEBP (+ / −) mice had a reduction of hippocampal heme oxygenase-1 (HO-1) expression compared to diabetic wild-type mice. In particular, we found that TonEBP bound to the LCN2 promoter in the diabetic hippocampus, and this binding was abolished by TonEBP haploinsufficiency. Furthermore, TonEBP knockdown attenuated LCN2 expression in lipopolysaccharide/high glucose-treated mouse hippocampal HT22 cells. Conclusions These findings indicate that TonEBP may promote neuroinflammation and cognitive impairment via upregulation of LCN2 in diabetic mice. |
| first_indexed | 2024-12-23T04:10:52Z |
| format | Article |
| id | doaj.art-e9976abfada3468c8aeb352b2c71aff3 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-23T04:10:52Z |
| publishDate | 2021-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-e9976abfada3468c8aeb352b2c71aff32022-12-21T18:00:30ZengBMCJournal of Neuroinflammation1742-20942021-11-0118111810.1186/s12974-021-02331-8Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2Eun Ae Jeong0Jaewoong Lee1Hyun Joo Shin2Jong Youl Lee3Kyung Eun Kim4Hyeong Seok An5Deok Ryong Kim6Kyu Yeong Choi7Kun Ho Lee8Gu Seob Roh9Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityDepartment of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityDepartment of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityDepartment of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityDepartment of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityDepartment of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityDepartment of Biochemistry, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityGwangju Alzheimer’s Disease and Related Dementia Cohort Research Center, Chosun UniversityGwangju Alzheimer’s Disease and Related Dementia Cohort Research Center, Chosun UniversityDepartment of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityAbstract Background Diabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. However, the precise role of TonEBP in the diabetic brain is not fully understood. Methods We employed a high-fat diet (HFD)-only fed mice or HFD/streptozotocin (STZ)-treated mice in our diabetic mouse models. Circulating TonEBP and lipocalin-2 (LCN2) levels were measured in type 2 diabetic subjects. TonEBP haploinsufficient mice were used to investigate the role of TonEBP in HFD/STZ-induced diabetic mice. In addition, RAW 264.7 macrophages were given a lipopolysaccharide (LPS)/high glucose (HG) treatment. Using a siRNA, we examined the effects of TonEBP knockdown on RAW264 cell’ medium/HG-treated mouse hippocampal HT22 cells. Results Circulating TonEBP and LCN2 levels were higher in experimental diabetic mice or type 2 diabetic patients with cognitive impairment. TonEBP haploinsufficiency ameliorated the diabetic phenotypes including adipose tissue macrophage infiltrations, neuroinflammation, blood–brain barrier leakage, and memory deficits. Systemic and hippocampal LCN2 proteins were reduced in diabetic mice by TonEBP haploinsufficiency. TonEBP (+ / −) mice had a reduction of hippocampal heme oxygenase-1 (HO-1) expression compared to diabetic wild-type mice. In particular, we found that TonEBP bound to the LCN2 promoter in the diabetic hippocampus, and this binding was abolished by TonEBP haploinsufficiency. Furthermore, TonEBP knockdown attenuated LCN2 expression in lipopolysaccharide/high glucose-treated mouse hippocampal HT22 cells. Conclusions These findings indicate that TonEBP may promote neuroinflammation and cognitive impairment via upregulation of LCN2 in diabetic mice.https://doi.org/10.1186/s12974-021-02331-8TonEBPLipocalin-2NeuroinflammationHippocampusDiabetes |
| spellingShingle | Eun Ae Jeong Jaewoong Lee Hyun Joo Shin Jong Youl Lee Kyung Eun Kim Hyeong Seok An Deok Ryong Kim Kyu Yeong Choi Kun Ho Lee Gu Seob Roh Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2 Journal of Neuroinflammation TonEBP Lipocalin-2 Neuroinflammation Hippocampus Diabetes |
| title | Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2 |
| title_full | Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2 |
| title_fullStr | Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2 |
| title_full_unstemmed | Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2 |
| title_short | Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2 |
| title_sort | tonicity responsive enhancer binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin 2 |
| topic | TonEBP Lipocalin-2 Neuroinflammation Hippocampus Diabetes |
| url | https://doi.org/10.1186/s12974-021-02331-8 |
| work_keys_str_mv | AT eunaejeong tonicityresponsiveenhancerbindingproteinpromotesdiabeticneuroinflammationandcognitiveimpairmentviaupregulationoflipocalin2 AT jaewoonglee tonicityresponsiveenhancerbindingproteinpromotesdiabeticneuroinflammationandcognitiveimpairmentviaupregulationoflipocalin2 AT hyunjooshin tonicityresponsiveenhancerbindingproteinpromotesdiabeticneuroinflammationandcognitiveimpairmentviaupregulationoflipocalin2 AT jongyoullee tonicityresponsiveenhancerbindingproteinpromotesdiabeticneuroinflammationandcognitiveimpairmentviaupregulationoflipocalin2 AT kyungeunkim tonicityresponsiveenhancerbindingproteinpromotesdiabeticneuroinflammationandcognitiveimpairmentviaupregulationoflipocalin2 AT hyeongseokan tonicityresponsiveenhancerbindingproteinpromotesdiabeticneuroinflammationandcognitiveimpairmentviaupregulationoflipocalin2 AT deokryongkim tonicityresponsiveenhancerbindingproteinpromotesdiabeticneuroinflammationandcognitiveimpairmentviaupregulationoflipocalin2 AT kyuyeongchoi tonicityresponsiveenhancerbindingproteinpromotesdiabeticneuroinflammationandcognitiveimpairmentviaupregulationoflipocalin2 AT kunholee tonicityresponsiveenhancerbindingproteinpromotesdiabeticneuroinflammationandcognitiveimpairmentviaupregulationoflipocalin2 AT guseobroh tonicityresponsiveenhancerbindingproteinpromotesdiabeticneuroinflammationandcognitiveimpairmentviaupregulationoflipocalin2 |