P2Y6 receptor-mediated signaling amplifies TLR-induced pro-inflammatory responses in microglia
TLR-induced signaling initiates inflammatory responses in cells of the innate immune system. These responses are amongst others characterized by the secretion of high levels of pro-inflammatory cytokines, which are tightly regulated and adapted to the microenvironment. Purinergic receptors are power...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.967951/full |
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| author | Raissa Timmerman Ella A. Zuiderwijk-Sick Jeffrey J. Bajramovic |
| author_facet | Raissa Timmerman Ella A. Zuiderwijk-Sick Jeffrey J. Bajramovic |
| author_sort | Raissa Timmerman |
| collection | DOAJ |
| description | TLR-induced signaling initiates inflammatory responses in cells of the innate immune system. These responses are amongst others characterized by the secretion of high levels of pro-inflammatory cytokines, which are tightly regulated and adapted to the microenvironment. Purinergic receptors are powerful modulators of TLR-induced responses, and we here characterized the effects of P2Y6 receptor (P2RY6)-mediated signaling on TLR responses of rhesus macaque primary bone marrow-derived macrophages (BMDM) and microglia, using the selective P2RY6 antagonist MRS2578. We demonstrate that P2RY6-mediated signaling enhances the levels of TLR-induced pro-inflammatory cytokines in microglia in particular. TLR1, 2, 4, 5 and 8-induced responses were all enhanced in microglia, whereas such effects were much less pronounced in BMDM from the same donors. Transcriptome analysis revealed that the overall contribution of P2RY6-mediated signaling to TLR-induced responses in microglia leads to an amplification of pro-inflammatory responses. Detailed target gene analysis predicts that P2RY6-mediated signaling regulates the expression of these genes via modulation of the activity of transcription factors NFAT, IRF and NF-κB. Interestingly, we found that the expression levels of heat shock proteins were strongly induced by inhibition of P2RY6-mediated signaling, both under homeostatic conditions as well as after TLR engagement. Together, our results shed new lights on the specific pro-inflammatory contribution of P2RY6-mediated signaling in neuroinflammation, which might open novel avenues to control brain inflammatory responses. |
| first_indexed | 2024-04-11T09:47:24Z |
| format | Article |
| id | doaj.art-76a5cd7d512a4d26bf9f10712ddcf5f5 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T09:47:24Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-76a5cd7d512a4d26bf9f10712ddcf5f52022-12-22T04:30:55ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-09-011310.3389/fimmu.2022.967951967951P2Y6 receptor-mediated signaling amplifies TLR-induced pro-inflammatory responses in microgliaRaissa TimmermanElla A. Zuiderwijk-SickJeffrey J. BajramovicTLR-induced signaling initiates inflammatory responses in cells of the innate immune system. These responses are amongst others characterized by the secretion of high levels of pro-inflammatory cytokines, which are tightly regulated and adapted to the microenvironment. Purinergic receptors are powerful modulators of TLR-induced responses, and we here characterized the effects of P2Y6 receptor (P2RY6)-mediated signaling on TLR responses of rhesus macaque primary bone marrow-derived macrophages (BMDM) and microglia, using the selective P2RY6 antagonist MRS2578. We demonstrate that P2RY6-mediated signaling enhances the levels of TLR-induced pro-inflammatory cytokines in microglia in particular. TLR1, 2, 4, 5 and 8-induced responses were all enhanced in microglia, whereas such effects were much less pronounced in BMDM from the same donors. Transcriptome analysis revealed that the overall contribution of P2RY6-mediated signaling to TLR-induced responses in microglia leads to an amplification of pro-inflammatory responses. Detailed target gene analysis predicts that P2RY6-mediated signaling regulates the expression of these genes via modulation of the activity of transcription factors NFAT, IRF and NF-κB. Interestingly, we found that the expression levels of heat shock proteins were strongly induced by inhibition of P2RY6-mediated signaling, both under homeostatic conditions as well as after TLR engagement. Together, our results shed new lights on the specific pro-inflammatory contribution of P2RY6-mediated signaling in neuroinflammation, which might open novel avenues to control brain inflammatory responses.https://www.frontiersin.org/articles/10.3389/fimmu.2022.967951/fullP2RY6microgliabone marrow-derived macrophagesTLRheat shock proteinsneuroinflammation |
| spellingShingle | Raissa Timmerman Ella A. Zuiderwijk-Sick Jeffrey J. Bajramovic P2Y6 receptor-mediated signaling amplifies TLR-induced pro-inflammatory responses in microglia Frontiers in Immunology P2RY6 microglia bone marrow-derived macrophages TLR heat shock proteins neuroinflammation |
| title | P2Y6 receptor-mediated signaling amplifies TLR-induced pro-inflammatory responses in microglia |
| title_full | P2Y6 receptor-mediated signaling amplifies TLR-induced pro-inflammatory responses in microglia |
| title_fullStr | P2Y6 receptor-mediated signaling amplifies TLR-induced pro-inflammatory responses in microglia |
| title_full_unstemmed | P2Y6 receptor-mediated signaling amplifies TLR-induced pro-inflammatory responses in microglia |
| title_short | P2Y6 receptor-mediated signaling amplifies TLR-induced pro-inflammatory responses in microglia |
| title_sort | p2y6 receptor mediated signaling amplifies tlr induced pro inflammatory responses in microglia |
| topic | P2RY6 microglia bone marrow-derived macrophages TLR heat shock proteins neuroinflammation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.967951/full |
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