Neuroinflammation aggravated by traumatic brain injury at high altitude is reversed by L-serine via NFAT1-mediated microglial polarization
Traumatic brain injury (TBI) is one of the main causes of disability and death, especially in plateau areas, where the degree of injury is often more serious than in plain areas. It is likely that high altitude (HA) aggravates neuroinflammation; however, prior studies are limited. This study was des...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-04-01
|
| Series: | Frontiers in Cellular Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2023.1152392/full |
| _version_ | 1797847172448780288 |
|---|---|
| author | Jinchun Liu Jinchun Liu Shunhua Peng Lisha Ye Yechao Sun Qiong Zhao Hua Wei Qianqian Luo Min He Min He Guohua Wang |
| author_facet | Jinchun Liu Jinchun Liu Shunhua Peng Lisha Ye Yechao Sun Qiong Zhao Hua Wei Qianqian Luo Min He Min He Guohua Wang |
| author_sort | Jinchun Liu |
| collection | DOAJ |
| description | Traumatic brain injury (TBI) is one of the main causes of disability and death, especially in plateau areas, where the degree of injury is often more serious than in plain areas. It is likely that high altitude (HA) aggravates neuroinflammation; however, prior studies are limited. This study was designed to evaluate the effects of HA on the degree of TBI and the neuroprotective effects and underlying mechanisms of L-serine against TBI at HA (HA-TBI). In in vivo experiments, wild-type mice and mice with Nfat1 (Nfat1−/−) deficiency in the C57BL/6 background were kept in a hypobaric chamber for 3 days under simulated conditions of 4,000 m, 6,000 m and 8,000 m above sea level. After leaving the chamber, the standardized TBI model was established immediately. Mice were then intraperitoneally injected with L-serine (342 mg.kg−1) 2 h after TBI and then daily for 5 days. Behavioral tests and histological analysis were assessed at different time points post TBI induction. In vitro, we applied primary cultured microglia for hypoxia treatment (1% O2 for 24 h). The major findings include the following: (1) with increasing altitude, the neurological function of TBI mice decreased, and the damage to cerebral gray matter and white matter became more significant, (2) L-serine significantly improved the sensorimotor function of mice, reversed the increase in brain lesion volume, and promoted the renovation of brain tissue after HA-TBI, (3) L-serine significantly decreased the activation of microglia and promoted microglia polarization toward the protective M2 phenotype both in vivo and in vitro, (4) L-serine significantly suppressed the expression of NFAT1 in mice after HA-TBI and inhibited NFAT1 expression in primary microglia after hypoxia, and (5) knockout of Nfat1 inhibited the inflammatory reaction caused by excessive activation of microglia, and L-serine lost its neuroprotective effect in Nfat1 knockout mice. The present study suggests that HA aggravates brain damage after TBI and that the damage also increases with increasing altitude. As an endogenous amino acid, L-serine may be a neuroprotective agent against HA-TBI, and suppression of NFAT1 in microglia is a potential therapy for neuroinflammation in the future. |
| first_indexed | 2024-04-09T18:06:59Z |
| format | Article |
| id | doaj.art-9569538712de401693315a2dd66092bd |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-04-09T18:06:59Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-9569538712de401693315a2dd66092bd2023-04-14T05:39:20ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022023-04-011710.3389/fncel.2023.11523921152392Neuroinflammation aggravated by traumatic brain injury at high altitude is reversed by L-serine via NFAT1-mediated microglial polarizationJinchun Liu0Jinchun Liu1Shunhua Peng2Lisha Ye3Yechao Sun4Qiong Zhao5Hua Wei6Qianqian Luo7Min He8Min He9Guohua Wang10Department of Medicine, Henan Vocational College of Nursing, Anyang, Henan, ChinaDepartment of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine, Nantong University, Nantong, Jiangsu, ChinaDepartment of Basic Medicine, Yiyang Medical College, Yiyang, Hunan, ChinaDepartment of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine, Nantong University, Nantong, Jiangsu, ChinaDepartment of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine, Nantong University, Nantong, Jiangsu, ChinaDepartment of Medicine, Henan Vocational College of Nursing, Anyang, Henan, ChinaDepartment of Medicine, Henan Vocational College of Nursing, Anyang, Henan, ChinaDepartment of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine, Nantong University, Nantong, Jiangsu, ChinaDepartment of Medicine, Henan Vocational College of Nursing, Anyang, Henan, ChinaDepartment of Scientific Research, Henan Vocational College of Nursing, Anyang, Henan, ChinaDepartment of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine, Nantong University, Nantong, Jiangsu, ChinaTraumatic brain injury (TBI) is one of the main causes of disability and death, especially in plateau areas, where the degree of injury is often more serious than in plain areas. It is likely that high altitude (HA) aggravates neuroinflammation; however, prior studies are limited. This study was designed to evaluate the effects of HA on the degree of TBI and the neuroprotective effects and underlying mechanisms of L-serine against TBI at HA (HA-TBI). In in vivo experiments, wild-type mice and mice with Nfat1 (Nfat1−/−) deficiency in the C57BL/6 background were kept in a hypobaric chamber for 3 days under simulated conditions of 4,000 m, 6,000 m and 8,000 m above sea level. After leaving the chamber, the standardized TBI model was established immediately. Mice were then intraperitoneally injected with L-serine (342 mg.kg−1) 2 h after TBI and then daily for 5 days. Behavioral tests and histological analysis were assessed at different time points post TBI induction. In vitro, we applied primary cultured microglia for hypoxia treatment (1% O2 for 24 h). The major findings include the following: (1) with increasing altitude, the neurological function of TBI mice decreased, and the damage to cerebral gray matter and white matter became more significant, (2) L-serine significantly improved the sensorimotor function of mice, reversed the increase in brain lesion volume, and promoted the renovation of brain tissue after HA-TBI, (3) L-serine significantly decreased the activation of microglia and promoted microglia polarization toward the protective M2 phenotype both in vivo and in vitro, (4) L-serine significantly suppressed the expression of NFAT1 in mice after HA-TBI and inhibited NFAT1 expression in primary microglia after hypoxia, and (5) knockout of Nfat1 inhibited the inflammatory reaction caused by excessive activation of microglia, and L-serine lost its neuroprotective effect in Nfat1 knockout mice. The present study suggests that HA aggravates brain damage after TBI and that the damage also increases with increasing altitude. As an endogenous amino acid, L-serine may be a neuroprotective agent against HA-TBI, and suppression of NFAT1 in microglia is a potential therapy for neuroinflammation in the future.https://www.frontiersin.org/articles/10.3389/fncel.2023.1152392/fulltraumatic brain injuryhigh altitudeL-serineneuroprotectionmicroglianuclear factor of activated T-cell 1 |
| spellingShingle | Jinchun Liu Jinchun Liu Shunhua Peng Lisha Ye Yechao Sun Qiong Zhao Hua Wei Qianqian Luo Min He Min He Guohua Wang Neuroinflammation aggravated by traumatic brain injury at high altitude is reversed by L-serine via NFAT1-mediated microglial polarization Frontiers in Cellular Neuroscience traumatic brain injury high altitude L-serine neuroprotection microglia nuclear factor of activated T-cell 1 |
| title | Neuroinflammation aggravated by traumatic brain injury at high altitude is reversed by L-serine via NFAT1-mediated microglial polarization |
| title_full | Neuroinflammation aggravated by traumatic brain injury at high altitude is reversed by L-serine via NFAT1-mediated microglial polarization |
| title_fullStr | Neuroinflammation aggravated by traumatic brain injury at high altitude is reversed by L-serine via NFAT1-mediated microglial polarization |
| title_full_unstemmed | Neuroinflammation aggravated by traumatic brain injury at high altitude is reversed by L-serine via NFAT1-mediated microglial polarization |
| title_short | Neuroinflammation aggravated by traumatic brain injury at high altitude is reversed by L-serine via NFAT1-mediated microglial polarization |
| title_sort | neuroinflammation aggravated by traumatic brain injury at high altitude is reversed by l serine via nfat1 mediated microglial polarization |
| topic | traumatic brain injury high altitude L-serine neuroprotection microglia nuclear factor of activated T-cell 1 |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2023.1152392/full |
| work_keys_str_mv | AT jinchunliu neuroinflammationaggravatedbytraumaticbraininjuryathighaltitudeisreversedbylserinevianfat1mediatedmicroglialpolarization AT jinchunliu neuroinflammationaggravatedbytraumaticbraininjuryathighaltitudeisreversedbylserinevianfat1mediatedmicroglialpolarization AT shunhuapeng neuroinflammationaggravatedbytraumaticbraininjuryathighaltitudeisreversedbylserinevianfat1mediatedmicroglialpolarization AT lishaye neuroinflammationaggravatedbytraumaticbraininjuryathighaltitudeisreversedbylserinevianfat1mediatedmicroglialpolarization AT yechaosun neuroinflammationaggravatedbytraumaticbraininjuryathighaltitudeisreversedbylserinevianfat1mediatedmicroglialpolarization AT qiongzhao neuroinflammationaggravatedbytraumaticbraininjuryathighaltitudeisreversedbylserinevianfat1mediatedmicroglialpolarization AT huawei neuroinflammationaggravatedbytraumaticbraininjuryathighaltitudeisreversedbylserinevianfat1mediatedmicroglialpolarization AT qianqianluo neuroinflammationaggravatedbytraumaticbraininjuryathighaltitudeisreversedbylserinevianfat1mediatedmicroglialpolarization AT minhe neuroinflammationaggravatedbytraumaticbraininjuryathighaltitudeisreversedbylserinevianfat1mediatedmicroglialpolarization AT minhe neuroinflammationaggravatedbytraumaticbraininjuryathighaltitudeisreversedbylserinevianfat1mediatedmicroglialpolarization AT guohuawang neuroinflammationaggravatedbytraumaticbraininjuryathighaltitudeisreversedbylserinevianfat1mediatedmicroglialpolarization |