TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway
Abstract Background Microglia, the innate immune cells in the central nervous system, play an essential role in brain homeostasis, neuroinflammation and brain infections. Dysregulated microglia, on the other hand, are associated with neurodegenerative diseases, yet the mechanisms underlying pro-infl...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-10-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02619-3 |
| _version_ | 1817983936323649536 |
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| author | Rong Li Jing Zhang Qiong Wang Meng Cheng Bin Lin |
| author_facet | Rong Li Jing Zhang Qiong Wang Meng Cheng Bin Lin |
| author_sort | Rong Li |
| collection | DOAJ |
| description | Abstract Background Microglia, the innate immune cells in the central nervous system, play an essential role in brain homeostasis, neuroinflammation and brain infections. Dysregulated microglia, on the other hand, are associated with neurodegenerative diseases, yet the mechanisms underlying pro-inflammatory gene expression in microglia are incompletely understood. Methods We investigated the role of the actin-associated protein tropomyosin 1 (TPM1) in regulating pro-inflammatory phenotype of microglia in the retina by using a combination of cell culture, immunocytochemistry, Western blot, qPCR, TUNEL, RNA sequencing and electroretinogram analysis. TREM2−/− mice were used to investigate whether TPM1 regulated pro-inflammatory responses downstream of TREM2. To conditionally deplete microglia, we backcrossed CX3CR1CreER mice with Rosa26iDTR mice to generate CX3CR1CreER:Rosa26iDTR mice. Results We revealed a vital role for TPM1 in regulating pro-inflammatory phenotype of microglia. We found that TPM1 drove LPS-induced inflammation and neuronal death in the retina via the PKA/CREB pathway. TPM1 knockdown ameliorated LPS-induced inflammation in WT retinas yet exaggerated the inflammation in TREM2−/− retinas. RNA sequencing revealed that genes associated with M1 microglia and A1 astrocytes were significantly downregulated in LPS-treated WT retinas but upregulated in LPS-treated TREM2−/− retinas after TPM1 knockdown. Mechanistically, we demonstrated that CREB activated by TPM1 knockdown mediated anti-inflammatory genes in LPS-treated WT retinas but pro-inflammatory genes in LPS-treated TREM2−/− retinas, suggesting a novel role for TREM2 as a brake on TPM1-mediated inflammation. Furthermore, we identified that TPM1 regulated inflammation downstream of TREM2 and in a microglia-dependent manner. Conclusions We demonstrate that TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway. Our findings suggest that TPM1 could be a potential target for therapeutic intervention in brain diseases. |
| first_indexed | 2024-04-13T23:39:21Z |
| format | Article |
| id | doaj.art-d71a20403b2b4de2be519602903f243e |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-13T23:39:21Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-d71a20403b2b4de2be519602903f243e2022-12-22T02:24:36ZengBMCJournal of Neuroinflammation1742-20942022-10-0119112210.1186/s12974-022-02619-3TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathwayRong Li0Jing Zhang1Qiong Wang2Meng Cheng3Bin Lin4School of Optometry, The Hong Kong Polytechnic UniversitySchool of Optometry, The Hong Kong Polytechnic UniversityCentre for Eye and Vision Research (CEVR)School of Optometry, The Hong Kong Polytechnic UniversitySchool of Optometry, The Hong Kong Polytechnic UniversityAbstract Background Microglia, the innate immune cells in the central nervous system, play an essential role in brain homeostasis, neuroinflammation and brain infections. Dysregulated microglia, on the other hand, are associated with neurodegenerative diseases, yet the mechanisms underlying pro-inflammatory gene expression in microglia are incompletely understood. Methods We investigated the role of the actin-associated protein tropomyosin 1 (TPM1) in regulating pro-inflammatory phenotype of microglia in the retina by using a combination of cell culture, immunocytochemistry, Western blot, qPCR, TUNEL, RNA sequencing and electroretinogram analysis. TREM2−/− mice were used to investigate whether TPM1 regulated pro-inflammatory responses downstream of TREM2. To conditionally deplete microglia, we backcrossed CX3CR1CreER mice with Rosa26iDTR mice to generate CX3CR1CreER:Rosa26iDTR mice. Results We revealed a vital role for TPM1 in regulating pro-inflammatory phenotype of microglia. We found that TPM1 drove LPS-induced inflammation and neuronal death in the retina via the PKA/CREB pathway. TPM1 knockdown ameliorated LPS-induced inflammation in WT retinas yet exaggerated the inflammation in TREM2−/− retinas. RNA sequencing revealed that genes associated with M1 microglia and A1 astrocytes were significantly downregulated in LPS-treated WT retinas but upregulated in LPS-treated TREM2−/− retinas after TPM1 knockdown. Mechanistically, we demonstrated that CREB activated by TPM1 knockdown mediated anti-inflammatory genes in LPS-treated WT retinas but pro-inflammatory genes in LPS-treated TREM2−/− retinas, suggesting a novel role for TREM2 as a brake on TPM1-mediated inflammation. Furthermore, we identified that TPM1 regulated inflammation downstream of TREM2 and in a microglia-dependent manner. Conclusions We demonstrate that TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway. Our findings suggest that TPM1 could be a potential target for therapeutic intervention in brain diseases.https://doi.org/10.1186/s12974-022-02619-3RetinaTropomyosin 1InflammationTREM2CREB |
| spellingShingle | Rong Li Jing Zhang Qiong Wang Meng Cheng Bin Lin TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway Journal of Neuroinflammation Retina Tropomyosin 1 Inflammation TREM2 CREB |
| title | TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway |
| title_full | TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway |
| title_fullStr | TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway |
| title_full_unstemmed | TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway |
| title_short | TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway |
| title_sort | tpm1 mediates inflammation downstream of trem2 via the pka creb signaling pathway |
| topic | Retina Tropomyosin 1 Inflammation TREM2 CREB |
| url | https://doi.org/10.1186/s12974-022-02619-3 |
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