The <i>TREM2</i> H157Y Variant Influences Microglial Phagocytosis, Polarization, and Inflammatory Cytokine Release
Previously, we reported that H157Y, a rare coding variant on exon 3 of the triggering receptor expressed on myeloid cells 2 gene (<i>TREM2</i>), was associated with Alzheimer’s disease (AD) risk in a Han Chinese population. To date, how this variant increases AD risk has remained unclear...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-04-01
|
| Series: | Brain Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3425/13/4/642 |
| _version_ | 1797606137582845952 |
|---|---|
| author | Xin-Xin Fu Shuai-Yu Chen Hui-Wen Lian Yang Deng Rui Duan Ying-Dong Zhang Teng Jiang |
| author_facet | Xin-Xin Fu Shuai-Yu Chen Hui-Wen Lian Yang Deng Rui Duan Ying-Dong Zhang Teng Jiang |
| author_sort | Xin-Xin Fu |
| collection | DOAJ |
| description | Previously, we reported that H157Y, a rare coding variant on exon 3 of the triggering receptor expressed on myeloid cells 2 gene (<i>TREM2</i>), was associated with Alzheimer’s disease (AD) risk in a Han Chinese population. To date, how this variant increases AD risk has remained unclear. In this study, using CRISPR-Cas9-engineered BV2 microglia, we tried to investigate the influence of the <i>Trem2</i> H157Y variant on AD-related microglial functions. For the first time, we revealed that the <i>Trem2</i> H157Y variant inhibits microglial phagocytosis of amyloid-β, promotes M1-type polarization of microglia, and facilitates microglial release of inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. These findings provide new insights into the cellular mechanisms by which the <i>TREM2</i> H157Y variant elevates the risk of AD. |
| first_indexed | 2024-03-11T05:11:03Z |
| format | Article |
| id | doaj.art-6753a3b3658c463196572f60811364e9 |
| institution | Directory Open Access Journal |
| issn | 2076-3425 |
| language | English |
| last_indexed | 2024-03-11T05:11:03Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Brain Sciences |
| spelling | doaj.art-6753a3b3658c463196572f60811364e92023-11-17T18:33:03ZengMDPI AGBrain Sciences2076-34252023-04-0113464210.3390/brainsci13040642The <i>TREM2</i> H157Y Variant Influences Microglial Phagocytosis, Polarization, and Inflammatory Cytokine ReleaseXin-Xin Fu0Shuai-Yu Chen1Hui-Wen Lian2Yang Deng3Rui Duan4Ying-Dong Zhang5Teng Jiang6Department of Neurology, Nanjing First Hospital, China Pharmaceutical University, No.639 Longmian Road, Nanjing 211100, ChinaDepartment of Neurology, Nanjing First Hospital, Nanjing Medical University, No.68 Changle Road, Nanjing 210006, ChinaDepartment of Neurology, Nanjing First Hospital, Nanjing Medical University, No.68 Changle Road, Nanjing 210006, ChinaDepartment of Neurology, Nanjing First Hospital, China Pharmaceutical University, No.639 Longmian Road, Nanjing 211100, ChinaDepartment of Neurology, Nanjing First Hospital, China Pharmaceutical University, No.639 Longmian Road, Nanjing 211100, ChinaDepartment of Neurology, Nanjing First Hospital, China Pharmaceutical University, No.639 Longmian Road, Nanjing 211100, ChinaDepartment of Neurology, Nanjing First Hospital, Nanjing Medical University, No.68 Changle Road, Nanjing 210006, ChinaPreviously, we reported that H157Y, a rare coding variant on exon 3 of the triggering receptor expressed on myeloid cells 2 gene (<i>TREM2</i>), was associated with Alzheimer’s disease (AD) risk in a Han Chinese population. To date, how this variant increases AD risk has remained unclear. In this study, using CRISPR-Cas9-engineered BV2 microglia, we tried to investigate the influence of the <i>Trem2</i> H157Y variant on AD-related microglial functions. For the first time, we revealed that the <i>Trem2</i> H157Y variant inhibits microglial phagocytosis of amyloid-β, promotes M1-type polarization of microglia, and facilitates microglial release of inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. These findings provide new insights into the cellular mechanisms by which the <i>TREM2</i> H157Y variant elevates the risk of AD.https://www.mdpi.com/2076-3425/13/4/642Alzheimer’s disease<i>TREM2</i>H157Y variantamyloid-βCRISPR-Cas9microglia |
| spellingShingle | Xin-Xin Fu Shuai-Yu Chen Hui-Wen Lian Yang Deng Rui Duan Ying-Dong Zhang Teng Jiang The <i>TREM2</i> H157Y Variant Influences Microglial Phagocytosis, Polarization, and Inflammatory Cytokine Release Brain Sciences Alzheimer’s disease <i>TREM2</i> H157Y variant amyloid-β CRISPR-Cas9 microglia |
| title | The <i>TREM2</i> H157Y Variant Influences Microglial Phagocytosis, Polarization, and Inflammatory Cytokine Release |
| title_full | The <i>TREM2</i> H157Y Variant Influences Microglial Phagocytosis, Polarization, and Inflammatory Cytokine Release |
| title_fullStr | The <i>TREM2</i> H157Y Variant Influences Microglial Phagocytosis, Polarization, and Inflammatory Cytokine Release |
| title_full_unstemmed | The <i>TREM2</i> H157Y Variant Influences Microglial Phagocytosis, Polarization, and Inflammatory Cytokine Release |
| title_short | The <i>TREM2</i> H157Y Variant Influences Microglial Phagocytosis, Polarization, and Inflammatory Cytokine Release |
| title_sort | i trem2 i h157y variant influences microglial phagocytosis polarization and inflammatory cytokine release |
| topic | Alzheimer’s disease <i>TREM2</i> H157Y variant amyloid-β CRISPR-Cas9 microglia |
| url | https://www.mdpi.com/2076-3425/13/4/642 |
| work_keys_str_mv | AT xinxinfu theitrem2ih157yvariantinfluencesmicroglialphagocytosispolarizationandinflammatorycytokinerelease AT shuaiyuchen theitrem2ih157yvariantinfluencesmicroglialphagocytosispolarizationandinflammatorycytokinerelease AT huiwenlian theitrem2ih157yvariantinfluencesmicroglialphagocytosispolarizationandinflammatorycytokinerelease AT yangdeng theitrem2ih157yvariantinfluencesmicroglialphagocytosispolarizationandinflammatorycytokinerelease AT ruiduan theitrem2ih157yvariantinfluencesmicroglialphagocytosispolarizationandinflammatorycytokinerelease AT yingdongzhang theitrem2ih157yvariantinfluencesmicroglialphagocytosispolarizationandinflammatorycytokinerelease AT tengjiang theitrem2ih157yvariantinfluencesmicroglialphagocytosispolarizationandinflammatorycytokinerelease AT xinxinfu itrem2ih157yvariantinfluencesmicroglialphagocytosispolarizationandinflammatorycytokinerelease AT shuaiyuchen itrem2ih157yvariantinfluencesmicroglialphagocytosispolarizationandinflammatorycytokinerelease AT huiwenlian itrem2ih157yvariantinfluencesmicroglialphagocytosispolarizationandinflammatorycytokinerelease AT yangdeng itrem2ih157yvariantinfluencesmicroglialphagocytosispolarizationandinflammatorycytokinerelease AT ruiduan itrem2ih157yvariantinfluencesmicroglialphagocytosispolarizationandinflammatorycytokinerelease AT yingdongzhang itrem2ih157yvariantinfluencesmicroglialphagocytosispolarizationandinflammatorycytokinerelease AT tengjiang itrem2ih157yvariantinfluencesmicroglialphagocytosispolarizationandinflammatorycytokinerelease |