mTOR downregulation promotes anti-inflammatory responses via the CCL3-CCR5 axis in hypoxic retinopathy
Hypoxic retinopathies, including diabetic retinopathy, are major contributors to vision impairment, mainly due to accelerated angiogenesis and inflammation. Previously, we demonstrated that AAV2-shmTOR, effective across distinct species, holds therapeutic promise by modulating the activated mTOR pat...
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050124002201 |
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| author | Tae Kwon Moon Im Kyeung Kang Kyoung Jin Lee Ji Hyun Kim Hee Jong Kim A. Reum Han Ha-Na Woo Joo Yong Lee Jun-Sub Choi Keerang Park Heuiran Lee |
| author_facet | Tae Kwon Moon Im Kyeung Kang Kyoung Jin Lee Ji Hyun Kim Hee Jong Kim A. Reum Han Ha-Na Woo Joo Yong Lee Jun-Sub Choi Keerang Park Heuiran Lee |
| author_sort | Tae Kwon Moon |
| collection | DOAJ |
| description | Hypoxic retinopathies, including diabetic retinopathy, are major contributors to vision impairment, mainly due to accelerated angiogenesis and inflammation. Previously, we demonstrated that AAV2-shmTOR, effective across distinct species, holds therapeutic promise by modulating the activated mTOR pathway, yet its mechanisms for reducing inflammation remain largely unexplored. To investigate AAV2-shmTOR’s impact on atypical inflammation in these conditions, we employed an in vivo model of oxygen-induced retinopathy and an in vitro model using rMC1 Müller cells. AAV2-shmTOR notably decreased mTOR expression in rMC1 cells under hypoxic conditions, as verified by co-staining for mTOR and glial fibrillary acidic protein (GFAP). It effectively interrupted the activation of mTOR signaling triggered by hypoxia. It diminished the secretion of CCL3 from rMC1 cells, consequently reducing microglial migration in response to conditioned media from AAV2-shmTOR-treated rMC1 cells. Notably, the virus lowered CCL3 expression in Müller cells and reduced the presence of CCR5-positive microglia in vivo, indicating its effectiveness in targeted inflammation management via the CCL3-CCR5 pathway. These findings thus highlight the potential of AAV2-shmTOR to exert anti-inflammatory effects by influencing the mTOR and subsequent CCL3-CCR5 pathways in hypoxic retinopathies, presenting a novel therapeutic approach for retinal diseases marked by hypoxia-driven inflammation. |
| format | Article |
| id | doaj-art-0b1a70f0bae04f0aad044b54c57f430e |
| institution | Kabale University |
| issn | 2329-0501 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj-art-0b1a70f0bae04f0aad044b54c57f430e2025-01-21T04:13:08ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012025-03-01331101404mTOR downregulation promotes anti-inflammatory responses via the CCL3-CCR5 axis in hypoxic retinopathyTae Kwon Moon0Im Kyeung Kang1Kyoung Jin Lee2Ji Hyun Kim3Hee Jong Kim4A. Reum Han5Ha-Na Woo6Joo Yong Lee7Jun-Sub Choi8Keerang Park9Heuiran Lee10Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Microbiology, University of Ulsan, College of Medicine, Seoul, Republic of KoreaAsan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Microbiology, University of Ulsan, College of Medicine, Seoul, Republic of KoreaDepartment of Microbiology, University of Ulsan, College of Medicine, Seoul, Republic of Korea; Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Republic of KoreaDepartment of Microbiology, University of Ulsan, College of Medicine, Seoul, Republic of Korea; Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Republic of KoreaInstitute of New Drug Development Research, CdmoGen Co., Ltd., Seoul 05854, Republic of KoreaAsan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Biochemistry & Molecular Biology, University of Ulsan College of Medicine, Seoul, Republic of KoreaBio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Biochemistry & Molecular Biology, University of Ulsan College of Medicine, Seoul, Republic of KoreaBio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Ophthalmology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of KoreaInstitute of New Drug Development Research, CdmoGen Co., Ltd., Seoul 05854, Republic of KoreaInstitute of New Drug Development Research, CdmoGen Co., Ltd., Seoul 05854, Republic of Korea; Corresponding author: Keerang Park, Institute of New Drug Development Research, CdmoGen Co., Ltd., Seoul 05854, Republic of Korea.Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Microbiology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea; Corresponding author: Heuiran Lee, Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Republic of Korea.Hypoxic retinopathies, including diabetic retinopathy, are major contributors to vision impairment, mainly due to accelerated angiogenesis and inflammation. Previously, we demonstrated that AAV2-shmTOR, effective across distinct species, holds therapeutic promise by modulating the activated mTOR pathway, yet its mechanisms for reducing inflammation remain largely unexplored. To investigate AAV2-shmTOR’s impact on atypical inflammation in these conditions, we employed an in vivo model of oxygen-induced retinopathy and an in vitro model using rMC1 Müller cells. AAV2-shmTOR notably decreased mTOR expression in rMC1 cells under hypoxic conditions, as verified by co-staining for mTOR and glial fibrillary acidic protein (GFAP). It effectively interrupted the activation of mTOR signaling triggered by hypoxia. It diminished the secretion of CCL3 from rMC1 cells, consequently reducing microglial migration in response to conditioned media from AAV2-shmTOR-treated rMC1 cells. Notably, the virus lowered CCL3 expression in Müller cells and reduced the presence of CCR5-positive microglia in vivo, indicating its effectiveness in targeted inflammation management via the CCL3-CCR5 pathway. These findings thus highlight the potential of AAV2-shmTOR to exert anti-inflammatory effects by influencing the mTOR and subsequent CCL3-CCR5 pathways in hypoxic retinopathies, presenting a novel therapeutic approach for retinal diseases marked by hypoxia-driven inflammation.http://www.sciencedirect.com/science/article/pii/S2329050124002201retinopathyhypoxiagene therapyadeno-associated virusmTORsmall interfering RNA |
| spellingShingle | Tae Kwon Moon Im Kyeung Kang Kyoung Jin Lee Ji Hyun Kim Hee Jong Kim A. Reum Han Ha-Na Woo Joo Yong Lee Jun-Sub Choi Keerang Park Heuiran Lee mTOR downregulation promotes anti-inflammatory responses via the CCL3-CCR5 axis in hypoxic retinopathy Molecular Therapy: Methods & Clinical Development retinopathy hypoxia gene therapy adeno-associated virus mTOR small interfering RNA |
| title | mTOR downregulation promotes anti-inflammatory responses via the CCL3-CCR5 axis in hypoxic retinopathy |
| title_full | mTOR downregulation promotes anti-inflammatory responses via the CCL3-CCR5 axis in hypoxic retinopathy |
| title_fullStr | mTOR downregulation promotes anti-inflammatory responses via the CCL3-CCR5 axis in hypoxic retinopathy |
| title_full_unstemmed | mTOR downregulation promotes anti-inflammatory responses via the CCL3-CCR5 axis in hypoxic retinopathy |
| title_short | mTOR downregulation promotes anti-inflammatory responses via the CCL3-CCR5 axis in hypoxic retinopathy |
| title_sort | mtor downregulation promotes anti inflammatory responses via the ccl3 ccr5 axis in hypoxic retinopathy |
| topic | retinopathy hypoxia gene therapy adeno-associated virus mTOR small interfering RNA |
| url | http://www.sciencedirect.com/science/article/pii/S2329050124002201 |
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