Neutrophil-inflicted vasculature damage suppresses immune-mediated optic nerve regeneration

Ryan Passino; Matthew C Finneran; Hannah Hafner; Qian Feng; Lucas D Huffman; Xiao-Feng Zhao; Craig N Johnson; Riki Kawaguchi; Juan A Oses-Prieto; Alma L Burlingame; Daniel H Geschwind; Larry I Benowitz; Roman J Giger

doi:10.1016/j.celrep.2024.113931

Neutrophil-inflicted vasculature damage suppresses immune-mediated optic nerve regeneration

Cell Rep. 2024 Mar 26;43(3):113931. doi: 10.1016/j.celrep.2024.113931. Epub 2024 Mar 15.

Affiliations

¹ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
² Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
³ Departments of Psychiatry and Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ University of California San Francisco, Department of Pharmaceutical Chemistry, San Francisco, CA 94158, USA.
⁵ Departments of Psychiatry and Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Departments of Neurosurgery and Ophthalmology, Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Boston Children's Hospital, Boston MA 02115, USA; Departmant of Ophthalmology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
⁷ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: rgiger@umich.edu.

PMID: 38492223
DOI: 10.1016/j.celrep.2024.113931

Abstract

In adult mammals, injured retinal ganglion cells (RGCs) fail to spontaneously regrow severed axons, resulting in permanent visual deficits. Robust axon growth, however, is observed after intra-ocular injection of particulate β-glucan isolated from yeast. Blood-borne myeloid cells rapidly respond to β-glucan, releasing numerous pro-regenerative factors. Unfortunately, the pro-regenerative effects are undermined by retinal damage inflicted by an overactive immune system. Here, we demonstrate that protection of the inflamed vasculature promotes immune-mediated RGC regeneration. In the absence of microglia, leakiness of the blood-retina barrier increases, pro-inflammatory neutrophils are elevated, and RGC regeneration is reduced. Functional ablation of the complement receptor 3 (CD11b/integrin-αM), but not the complement components C1q^-/- or C3^-/-, reduces ocular inflammation, protects the blood-retina barrier, and enhances RGC regeneration. Selective targeting of neutrophils with anti-Ly6G does not increase axogenic neutrophils but protects the blood-retina barrier and enhances RGC regeneration. Together, these findings reveal that protection of the inflamed vasculature promotes neuronal regeneration.

Keywords: CD11; CP: Neuroscience; axon regeneration; blood-retina barrier; microglia; neutrophils; retinal gangl retinal ganglion cells; vascular inflammation.

MeSH terms

Animals
Axons / physiology
Mammals
Nerve Regeneration / physiology
Neutrophils
Optic Nerve Injuries*
Retinal Ganglion Cells / physiology
beta-Glucans*

Substances

beta-Glucans