IGFBPL1 is a master driver of microglia homeostasis and resolution of neuroinflammation in glaucoma and brain tauopathy

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

Cell Reports (Aug 2023)

IGFBPL1 is a master driver of microglia homeostasis and resolution of neuroinflammation in glaucoma and brain tauopathy

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

Affiliations

Li Pan: Schepens 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, China
Kin-Sang Cho: Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
Xin Wei: Schepens 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, China
Fuyi Xu: Department 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, China
Anton Lennikov: Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
Guangan Hu: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Jing Tang: Schepens 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, China
Shuai Guo: Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
Julie Chen: Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
Emil Kriukov: Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
Robert Kyle: Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
Farris Elzaridi: Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
Shuhong Jiang: Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
Pierre A. Dromel: Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
Michael Young: Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
Petr Baranov: Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
Chi-Wai Do: School of Optometry, The Hong Kong Polytechnic University, Hong Kong 999077, China
Robert W. Williams: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
Jianzhu Chen: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Lu Lu: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Corresponding author
Dong Feng Chen: Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 8
p. 112889

Abstract

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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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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