Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver
ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1 (encoding MDA5) rescues embryonic lethality in ADAR1-deficient mice, they still experience early postnatal death, and removing other...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2024
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| Online Access: | https://hdl.handle.net/10356/179659 |
| _version_ | 1826128050363826176 |
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| author | Gan, Wei Liang Ren, Xi Ng, Vanessa Hui En Ng, Larry Song, Yangyang Tano, Vincent Han, Jian An, Omer Xie, Jinghe Ng, Bryan Y. L. Tay, Daryl Jin Tai Tang, Sze Jing Shen, Haoqing Khare, Shruti Chong, Kelvin Han Chung Young, Dan Yock Wu, Bin DasGupta, Ramanuj Chen, Leilei |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Gan, Wei Liang Ren, Xi Ng, Vanessa Hui En Ng, Larry Song, Yangyang Tano, Vincent Han, Jian An, Omer Xie, Jinghe Ng, Bryan Y. L. Tay, Daryl Jin Tai Tang, Sze Jing Shen, Haoqing Khare, Shruti Chong, Kelvin Han Chung Young, Dan Yock Wu, Bin DasGupta, Ramanuj Chen, Leilei |
| author_sort | Gan, Wei Liang |
| collection | NTU |
| description | ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1 (encoding MDA5) rescues embryonic lethality in ADAR1-deficient mice, they still experience early postnatal death, and removing other MDA5 signaling proteins does not yield the same rescue. Here, we show that ablation of MDA5 in a liver-specific Adar knockout (KO) murine model fails to rescue hepatic abnormalities caused by ADAR1 loss. Ifih1;Adar double KO (dKO) hepatocytes accumulate endogenous dsRNAs, leading to aberrant transition to a highly inflammatory state and recruitment of macrophages into dKO livers. Mechanistically, progranulin (PGRN) appears to mediate ADAR1 deficiency-induced liver pathology, promoting interferon signaling and attracting epidermal growth factor receptor (EGFR)+ macrophages into dKO liver, exacerbating hepatic inflammation. Notably, the PGRN-EGFR crosstalk communication and consequent immune responses are significantly repressed in ADAR1high tumors, revealing that pre-neoplastic or neoplastic cells can exploit ADAR1-dependent immune tolerance to facilitate immune evasion. |
| first_indexed | 2024-10-01T07:18:32Z |
| format | Journal Article |
| id | ntu-10356/179659 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:18:32Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1796592024-08-19T15:32:17Z Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver Gan, Wei Liang Ren, Xi Ng, Vanessa Hui En Ng, Larry Song, Yangyang Tano, Vincent Han, Jian An, Omer Xie, Jinghe Ng, Bryan Y. L. Tay, Daryl Jin Tai Tang, Sze Jing Shen, Haoqing Khare, Shruti Chong, Kelvin Han Chung Young, Dan Yock Wu, Bin DasGupta, Ramanuj Chen, Leilei School of Biological Sciences NTU Institute of Structural Biology Medicine, Health and Life Sciences Immunosuppression Liver inflammation ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1 (encoding MDA5) rescues embryonic lethality in ADAR1-deficient mice, they still experience early postnatal death, and removing other MDA5 signaling proteins does not yield the same rescue. Here, we show that ablation of MDA5 in a liver-specific Adar knockout (KO) murine model fails to rescue hepatic abnormalities caused by ADAR1 loss. Ifih1;Adar double KO (dKO) hepatocytes accumulate endogenous dsRNAs, leading to aberrant transition to a highly inflammatory state and recruitment of macrophages into dKO livers. Mechanistically, progranulin (PGRN) appears to mediate ADAR1 deficiency-induced liver pathology, promoting interferon signaling and attracting epidermal growth factor receptor (EGFR)+ macrophages into dKO liver, exacerbating hepatic inflammation. Notably, the PGRN-EGFR crosstalk communication and consequent immune responses are significantly repressed in ADAR1high tumors, revealing that pre-neoplastic or neoplastic cells can exploit ADAR1-dependent immune tolerance to facilitate immune evasion. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This work was supported by National Research Foundation, Singapore; the Singapore Ministry of Education (MOE) under its Research Centers of Excellence initiative; Singapore MOE Academic Research Fund (AcRF) Tier 2 grants (MOE2019 T2-1-083 and MOE2019-T2-2-008); an NMRC Clinician Scientist Individual Research Grant (MOH-001092-00); the Health and Biomedical Sciences Industry Alignment Fund Pre-Positioning (IAF-PP) (H20C6a0034); and NRF Competitive Research Program (CRP) grants (NRF-CRP26-2021-0001 and NRF-CRP26-2021-0005). 2024-08-14T06:46:32Z 2024-08-14T06:46:32Z 2024 Journal Article Gan, W. L., Ren, X., Ng, V. H. E., Ng, L., Song, Y., Tano, V., Han, J., An, O., Xie, J., Ng, B. Y. L., Tay, D. J. T., Tang, S. J., Shen, H., Khare, S., Chong, K. H. C., Young, D. Y., Wu, B., DasGupta, R. & Chen, L. (2024). Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver. Cell Reports, 43(7), 114400-. https://dx.doi.org/10.1016/j.celrep.2024.114400 2639-1856 https://hdl.handle.net/10356/179659 10.1016/j.celrep.2024.114400 38935501 2-s2.0-85196827401 7 43 114400 en MOE2019 T2-1-083 MOE2019-T2-2-008 MOH-001092-00 H20C6a0034 NRF-CRP26-2021-0001 NRF-CRP26-2021-0005 Cell Reports © 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Immunosuppression Liver inflammation Gan, Wei Liang Ren, Xi Ng, Vanessa Hui En Ng, Larry Song, Yangyang Tano, Vincent Han, Jian An, Omer Xie, Jinghe Ng, Bryan Y. L. Tay, Daryl Jin Tai Tang, Sze Jing Shen, Haoqing Khare, Shruti Chong, Kelvin Han Chung Young, Dan Yock Wu, Bin DasGupta, Ramanuj Chen, Leilei Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver |
| title | Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver |
| title_full | Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver |
| title_fullStr | Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver |
| title_full_unstemmed | Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver |
| title_short | Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver |
| title_sort | hepatocyte macrophage crosstalk via the pgrn egfr axis modulates adar1 mediated immunity in the liver |
| topic | Medicine, Health and Life Sciences Immunosuppression Liver inflammation |
| url | https://hdl.handle.net/10356/179659 |
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