IGFBPL1 is a master driver of microglia homeostasis and resolution of neuroinflammation in glaucoma and brain tauopathy
Summary: Microglia shift toward an inflammatory phenotype during aging that is thought to exacerbate age-related neurodegeneration. The molecular and cellular signals that resolve neuroinflammation post-injury are largely undefined. Here, we exploit systems genetics methods based on the extended BXD...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723009002 |
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| author | Li Pan Kin-Sang Cho Xin Wei Fuyi Xu Anton Lennikov Guangan Hu Jing Tang Shuai Guo Julie Chen Emil Kriukov Robert Kyle Farris Elzaridi Shuhong Jiang Pierre A. Dromel Michael Young Petr Baranov Chi-Wai Do Robert W. Williams Jianzhu Chen Lu Lu Dong Feng Chen |
| author_facet | Li Pan Kin-Sang Cho Xin Wei Fuyi Xu Anton Lennikov Guangan Hu Jing Tang Shuai Guo Julie Chen Emil Kriukov Robert Kyle Farris Elzaridi Shuhong Jiang Pierre A. Dromel Michael Young Petr Baranov Chi-Wai Do Robert W. Williams Jianzhu Chen Lu Lu Dong Feng Chen |
| author_sort | Li Pan |
| collection | DOAJ |
| description | Summary: Microglia shift toward an inflammatory phenotype during aging that is thought to exacerbate age-related neurodegeneration. The molecular and cellular signals that resolve neuroinflammation post-injury are largely undefined. Here, we exploit systems genetics methods based on the extended BXD murine reference family and identify IGFBPL1 as an upstream cis-regulator of microglia-specific genes to switch off inflammation. IGFBPL1 is expressed by mouse and human microglia, and higher levels of its expression resolve lipopolysaccharide-induced neuroinflammation by resetting the transcriptome signature back to a homeostatic state via IGF1R signaling. Conversely, IGFBPL1 deficiency or selective deletion of IGF1R in microglia shifts these cells to an inflammatory landscape and induces early manifestation of brain tauopathy and retinal neurodegeneration. Therapeutic administration of IGFBPL1 drives pro-homeostatic microglia and prevents glaucomatous neurodegeneration and vision loss in mice. These results identify IGFBPL1 as a master driver of the counter-inflammatory microglial modulator that presents an endogenous resolution of neuroinflammation to prevent neurodegeneration in eye and brain. |
| first_indexed | 2024-03-12T11:53:38Z |
| format | Article |
| id | doaj.art-55ab54bc0ed043058de1e9df498fb842 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-12T11:53:38Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-55ab54bc0ed043058de1e9df498fb8422023-08-31T05:02:04ZengElsevierCell Reports2211-12472023-08-01428112889IGFBPL1 is a master driver of microglia homeostasis and resolution of neuroinflammation in glaucoma and brain tauopathyLi Pan0Kin-Sang Cho1Xin Wei2Fuyi Xu3Anton Lennikov4Guangan Hu5Jing Tang6Shuai Guo7Julie Chen8Emil Kriukov9Robert Kyle10Farris Elzaridi11Shuhong Jiang12Pierre A. Dromel13Michael Young14Petr Baranov15Chi-Wai Do16Robert W. Williams17Jianzhu Chen18Lu Lu19Dong Feng Chen20Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA; School of Optometry, The Hong Kong Polytechnic University, Hong Kong 999077, ChinaSchepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USASchepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA; Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, ChinaDepartment of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, School of Pharmacy, Binzhou Medical University, Yantai, Shandong 264003, ChinaSchepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USAKoch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USASchepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA; Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, ChinaSchepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USASchepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USASchepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USASchepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USASchepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USASchepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USASchepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USASchepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USASchepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USASchool of Optometry, The Hong Kong Polytechnic University, Hong Kong 999077, ChinaDepartment of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USAKoch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USADepartment of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Corresponding authorSchepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA; Corresponding authorSummary: Microglia shift toward an inflammatory phenotype during aging that is thought to exacerbate age-related neurodegeneration. The molecular and cellular signals that resolve neuroinflammation post-injury are largely undefined. Here, we exploit systems genetics methods based on the extended BXD murine reference family and identify IGFBPL1 as an upstream cis-regulator of microglia-specific genes to switch off inflammation. IGFBPL1 is expressed by mouse and human microglia, and higher levels of its expression resolve lipopolysaccharide-induced neuroinflammation by resetting the transcriptome signature back to a homeostatic state via IGF1R signaling. Conversely, IGFBPL1 deficiency or selective deletion of IGF1R in microglia shifts these cells to an inflammatory landscape and induces early manifestation of brain tauopathy and retinal neurodegeneration. Therapeutic administration of IGFBPL1 drives pro-homeostatic microglia and prevents glaucomatous neurodegeneration and vision loss in mice. These results identify IGFBPL1 as a master driver of the counter-inflammatory microglial modulator that presents an endogenous resolution of neuroinflammation to prevent neurodegeneration in eye and brain.http://www.sciencedirect.com/science/article/pii/S2211124723009002CP: NeuroscienceCP: Immunology |
| spellingShingle | Li Pan Kin-Sang Cho Xin Wei Fuyi Xu Anton Lennikov Guangan Hu Jing Tang Shuai Guo Julie Chen Emil Kriukov Robert Kyle Farris Elzaridi Shuhong Jiang Pierre A. Dromel Michael Young Petr Baranov Chi-Wai Do Robert W. Williams Jianzhu Chen Lu Lu Dong Feng Chen IGFBPL1 is a master driver of microglia homeostasis and resolution of neuroinflammation in glaucoma and brain tauopathy Cell Reports CP: Neuroscience CP: Immunology |
| title | IGFBPL1 is a master driver of microglia homeostasis and resolution of neuroinflammation in glaucoma and brain tauopathy |
| title_full | IGFBPL1 is a master driver of microglia homeostasis and resolution of neuroinflammation in glaucoma and brain tauopathy |
| title_fullStr | IGFBPL1 is a master driver of microglia homeostasis and resolution of neuroinflammation in glaucoma and brain tauopathy |
| title_full_unstemmed | IGFBPL1 is a master driver of microglia homeostasis and resolution of neuroinflammation in glaucoma and brain tauopathy |
| title_short | IGFBPL1 is a master driver of microglia homeostasis and resolution of neuroinflammation in glaucoma and brain tauopathy |
| title_sort | igfbpl1 is a master driver of microglia homeostasis and resolution of neuroinflammation in glaucoma and brain tauopathy |
| topic | CP: Neuroscience CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723009002 |
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