M6A Modified miR‐31‐5p Suppresses M1 Macrophage Polarization and Autoimmune Dry Eye by Targeting P2RX7
Abstract The dysregulation of the M1/M2 macrophage balance plays a pivotal role in autoimmune diseases. However, the interplay between microRNAs (miRNAs) and N6‐methyladenosine (m6A) modulation in regulating this balance remains poorly understood. Here, a significant reduction in miR‐31‐5p levels is...
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2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202415341 |
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| author | Lu Zhao Xuejia Li Min Gao Lin Liu Binyun Ma Xun Liu Jiachen Zhang Ruoxuan Liu Bei Du Ruihua Wei Hong Nian |
| author_facet | Lu Zhao Xuejia Li Min Gao Lin Liu Binyun Ma Xun Liu Jiachen Zhang Ruoxuan Liu Bei Du Ruihua Wei Hong Nian |
| author_sort | Lu Zhao |
| collection | DOAJ |
| description | Abstract The dysregulation of the M1/M2 macrophage balance plays a pivotal role in autoimmune diseases. However, the interplay between microRNAs (miRNAs) and N6‐methyladenosine (m6A) modulation in regulating this balance remains poorly understood. Here, a significant reduction in miR‐31‐5p levels is observed in the lacrimal glands of rabbit autoimmune dacryoadenitis and the peripheral blood mononuclear cells (PBMCs) of Sjögren's syndrome (SS) dry eye patients. Overexpression of miR‐31‐5p exhibits preventive and therapeutic effects on rabbit autoimmune dacryoadenitis. Further investigation revealed that miR‐31‐5p overexpression significantly restored the M1/M2 macrophage balance both in vivo and in vitro. Mechanistically, miR‐31‐5p directly targets the P2x7 receptor (P2RX7), leading to the inactivation of p38 mitogen‐activated protein kinases (MAPK) signaling and reduced expression of M1 markers. Furthermore, methylated RNA immunoprecipitation and luciferase reporter assays demonstrated that fat mass and obesity‐associated protein (FTO)‐mediated m6A demethylation, which sustains pri‐miR‐31 stability, is responsible for the decreased miR‐31‐5p levels in autoimmune dry eye. Notably, PBMC samples from SS dry eye patients further support the link between reduced miR‐31‐5p levels and M1 macrophage activation observed in rabbits. Overall, these data highlight the critical role of the FTO/miR‐31‐5p/P2RX7/p38 MAPK axis in autoimmune inflammation, suggesting their potential as therapeutic targets for autoimmune dry eye. |
| format | Article |
| id | doaj-art-046ad8e717474eeba2fe9c187b152b15 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-046ad8e717474eeba2fe9c187b152b152025-08-20T02:56:12ZengWileyAdvanced Science2198-38442025-05-011217n/an/a10.1002/advs.202415341M6A Modified miR‐31‐5p Suppresses M1 Macrophage Polarization and Autoimmune Dry Eye by Targeting P2RX7Lu Zhao0Xuejia Li1Min Gao2Lin Liu3Binyun Ma4Xun Liu5Jiachen Zhang6Ruoxuan Liu7Bei Du8Ruihua Wei9Hong Nian10Tianjin Key Laboratory of Retinal Functions and Diseases Tianjin Branch of National Clinical Research Center for Ocular Disease Eye Institute and School of Optometry Tianjin Medical University Eye Hospital Tianjin 300384 ChinaTianjin Key Laboratory of Retinal Functions and Diseases Tianjin Branch of National Clinical Research Center for Ocular Disease Eye Institute and School of Optometry Tianjin Medical University Eye Hospital Tianjin 300384 ChinaTianjin Key Laboratory of Retinal Functions and Diseases Tianjin Branch of National Clinical Research Center for Ocular Disease Eye Institute and School of Optometry Tianjin Medical University Eye Hospital Tianjin 300384 ChinaTianjin Key Laboratory of Retinal Functions and Diseases Tianjin Branch of National Clinical Research Center for Ocular Disease Eye Institute and School of Optometry Tianjin Medical University Eye Hospital Tianjin 300384 ChinaDepartment of Medicine/Hematology Keck School of Medicine of the University of Southern California Los Angeles CA 90033 USATianjin Key Laboratory of Retinal Functions and Diseases Tianjin Branch of National Clinical Research Center for Ocular Disease Eye Institute and School of Optometry Tianjin Medical University Eye Hospital Tianjin 300384 ChinaTianjin Key Laboratory of Retinal Functions and Diseases Tianjin Branch of National Clinical Research Center for Ocular Disease Eye Institute and School of Optometry Tianjin Medical University Eye Hospital Tianjin 300384 ChinaTianjin Key Laboratory of Retinal Functions and Diseases Tianjin Branch of National Clinical Research Center for Ocular Disease Eye Institute and School of Optometry Tianjin Medical University Eye Hospital Tianjin 300384 ChinaTianjin Key Laboratory of Retinal Functions and Diseases Tianjin Branch of National Clinical Research Center for Ocular Disease Eye Institute and School of Optometry Tianjin Medical University Eye Hospital Tianjin 300384 ChinaTianjin Key Laboratory of Retinal Functions and Diseases Tianjin Branch of National Clinical Research Center for Ocular Disease Eye Institute and School of Optometry Tianjin Medical University Eye Hospital Tianjin 300384 ChinaTianjin Key Laboratory of Retinal Functions and Diseases Tianjin Branch of National Clinical Research Center for Ocular Disease Eye Institute and School of Optometry Tianjin Medical University Eye Hospital Tianjin 300384 ChinaAbstract The dysregulation of the M1/M2 macrophage balance plays a pivotal role in autoimmune diseases. However, the interplay between microRNAs (miRNAs) and N6‐methyladenosine (m6A) modulation in regulating this balance remains poorly understood. Here, a significant reduction in miR‐31‐5p levels is observed in the lacrimal glands of rabbit autoimmune dacryoadenitis and the peripheral blood mononuclear cells (PBMCs) of Sjögren's syndrome (SS) dry eye patients. Overexpression of miR‐31‐5p exhibits preventive and therapeutic effects on rabbit autoimmune dacryoadenitis. Further investigation revealed that miR‐31‐5p overexpression significantly restored the M1/M2 macrophage balance both in vivo and in vitro. Mechanistically, miR‐31‐5p directly targets the P2x7 receptor (P2RX7), leading to the inactivation of p38 mitogen‐activated protein kinases (MAPK) signaling and reduced expression of M1 markers. Furthermore, methylated RNA immunoprecipitation and luciferase reporter assays demonstrated that fat mass and obesity‐associated protein (FTO)‐mediated m6A demethylation, which sustains pri‐miR‐31 stability, is responsible for the decreased miR‐31‐5p levels in autoimmune dry eye. Notably, PBMC samples from SS dry eye patients further support the link between reduced miR‐31‐5p levels and M1 macrophage activation observed in rabbits. Overall, these data highlight the critical role of the FTO/miR‐31‐5p/P2RX7/p38 MAPK axis in autoimmune inflammation, suggesting their potential as therapeutic targets for autoimmune dry eye.https://doi.org/10.1002/advs.202415341m6Amacrophage polarizationmiR‐31‐5pp2x7 receptorsjogren's syndrome dry eye |
| spellingShingle | Lu Zhao Xuejia Li Min Gao Lin Liu Binyun Ma Xun Liu Jiachen Zhang Ruoxuan Liu Bei Du Ruihua Wei Hong Nian M6A Modified miR‐31‐5p Suppresses M1 Macrophage Polarization and Autoimmune Dry Eye by Targeting P2RX7 Advanced Science m6A macrophage polarization miR‐31‐5p p2x7 receptor sjogren's syndrome dry eye |
| title | M6A Modified miR‐31‐5p Suppresses M1 Macrophage Polarization and Autoimmune Dry Eye by Targeting P2RX7 |
| title_full | M6A Modified miR‐31‐5p Suppresses M1 Macrophage Polarization and Autoimmune Dry Eye by Targeting P2RX7 |
| title_fullStr | M6A Modified miR‐31‐5p Suppresses M1 Macrophage Polarization and Autoimmune Dry Eye by Targeting P2RX7 |
| title_full_unstemmed | M6A Modified miR‐31‐5p Suppresses M1 Macrophage Polarization and Autoimmune Dry Eye by Targeting P2RX7 |
| title_short | M6A Modified miR‐31‐5p Suppresses M1 Macrophage Polarization and Autoimmune Dry Eye by Targeting P2RX7 |
| title_sort | m6a modified mir 31 5p suppresses m1 macrophage polarization and autoimmune dry eye by targeting p2rx7 |
| topic | m6A macrophage polarization miR‐31‐5p p2x7 receptor sjogren's syndrome dry eye |
| url | https://doi.org/10.1002/advs.202415341 |
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