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

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

Free article

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

Ryan Passino et al. Cell Rep. 2024.

Free article

. 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.

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Conflict of interest statement

Declaration of interests Particulate and soluble β-(1,3)(1,6)-glucans were provided by ImmunoResearch, Inc., MN 55121, USA, under a collaborative research agreement. The PLX5622 compound was provided by Plexxikon, Inc., San Francisco, California, USA. Neither ImmunoResearch, Inc., nor Plexxikon, Inc., had any input in experimental design, data acquisition, interpretation, or presentation.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials

Miscellaneous