Microglia at Sites of Atrophy Restrict the Progression of Retinal Degeneration via Galectin-3 and Trem2 Interactions

Yu, Chen; Lad, Eleonora M.; Mathew, Rose; Littleton, Sejiro; Chen, Yun; Schlepckow, Kai; Degan, Simone; Chew, Lindsey A.; Amason, Joshua; Kalnitsky, Joan; Rickman, Catherine Bowes; Proia, Alan D.; Colonna, Marco; Haass, Christian; Saban, Daniel R.

doi:10.1101/2023.07.19.549403

Cited by 3 publications

(3 citation statements)

References 92 publications

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“…Galectin-3-expressing phagocytic macrophages infiltrate into diabetic brains 36 suggesting that the peripheral nerve infiltrating macrophages may also be phagocytic, and that they may be neuroprotective by virtue of clearing debris or excess fatty acids in the nerve. Galectin-3 is expressed by microglia at sites of brain atrophy and is protective against retinal degeneration 29 . Another gene highly expressed by the nerve infiltrating macrophages encodes Thrombospondin-1, another neuroprotective mediator 27 .…”

Section: Discussionmentioning

confidence: 99%

“…3f). From the gene expression programs of the macrophages in diabetic nerves, we identified differentially expressed genes between recMacs and resMacs and found many injury-responsive genes such as Fn1 and Chil3 4 , as well as genes responsible for lipid uptake such as Lpl 24–27 and genes previously shown to promote nerve regeneration such as Lgals3 and Thbs1 27–29 (Fig. 4e).…”

Section: Main Textmentioning

confidence: 99%

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Macrophages protect against sensory axon degeneration in diabetic neuropathy

Hakim,

Jain,

Petrova

et al. 2024

Preprint

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Diabetic peripheral neuropathy (DPN) is the most common peripheral nervous system complication of diabetes, causing sensory loss and debilitating neuropathic pain. Although the onset and progression of DPN have been linked with dyslipidemia and hyperglycemia, the contribution of inflammation in the pathogenesis of DPN has not been investigated. Here, we use a High Fat High Fructose Diet (HFHFD) to model DPN and the diabetic metabolic syndrome in mice. Diabetic mice develop persistent heat hypoalgesia after three months, but a reduction in epidermal skin innervation only manifests at 6 months. Using single-cell sequencing, we find that CCR2+ macrophages infiltrate the sciatic nerves of diabetic mice well before axonal degeneration is observed. We show that these infiltrating macrophages share gene expression similarities with nerve crush-induced macrophages and express neurodegeneration-associated microglia marker genes although there is no axon loss or demyelination yet. Inhibiting this macrophage recruitment in diabetic mice by genetically or pharmacologically blocking CCR2 signaling results in a more severe heat hypoalgesia and accelerated skin denervation. These findings identify a novel neuroprotective recruitment of macrophages into peripheral nerves of diabetic mice that delays the onset of terminal axonal degeneration, thereby reducing sensory loss. Potentiating and sustaining this early neuroprotective immune response in patients represents, therefore, a potential means to reduce or prevent DPN.

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Section: Discussionmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Macrophages protect against sensory axon degeneration in diabetic neuropathy

Hakim,

Jain,

Petrova

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Galectin-3expressing phagocytic macrophages infiltrate into diabetic brains 36 suggesting that the peripheral nerve infiltrating macrophages may also be phagocytic, and that they may be neuroprotective by virtue of clearing debris or excess fatty acids in the nerve. Galectin-3 is expressed by microglia at sites of brain atrophy and is protective against retinal degeneration 29 . Another gene highly expressed by the nerve infiltrating macrophages encodes Thrombospondin-1, another neuroprotective mediator 27 .…”

Section: Discussionmentioning

confidence: 99%

Macrophages protect against sensory axon degeneration in diabetic neuropathy

Woolf,

Hakim,

Jain

et al. 2024

Preprint

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Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, causing sensory loss and debilitating neuropathic pain1,2. Although the onset and progression of DPN have been linked with dyslipidemia and hyperglycemia3, the contribution of inflammation in the pathogenesis of DPN has not been investigated. Here, we use a High Fat High Fructose Diet (HFHFD) to model DPN and its metabolic syndrome in mice. Diabetic mice develop persistent heat hypoalgesia after three months, but a reduction in epidermal skin innervation only manifests at 6 months. Using single-cell sequencing, we find that CCR2+ macrophages infiltrate the sciatic nerves of diabetic mice well before axonal degeneration is detectable. We show that these infiltrating macrophages share gene expression similarities with nerve crush-induced macrophages4 and express neurodegeneration-associated microglia marker genes5 although there is no axon loss or demyelination yet. Inhibiting this macrophage recruitment in diabetic mice by genetically or pharmacologically blocking CCR2 signaling results in a more severe heat hypoalgesia and accelerated skin denervation. These findings reveal a novel neuroprotective recruitment of macrophages into peripheral nerves of diabetic mice that delays the onset of terminal axonal degeneration, thereby reducing sensory loss. Potentiating and sustaining this early neuroprotective immune response in patients represents, therefore, a potential means to reduce or prevent DPN.

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Distinct mouse models of Stargardt disease display differences in pharmacological targeting of ceramides and inflammatory responses

Engfer,

Lewandowski,

Dong

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in many visual cycle enzymes in photoreceptors and retinal pigment epithelium (RPE) cells can lead to the chronic accumulation of toxic retinoid byproducts, which poison photoreceptors and the underlying RPE if left unchecked. Without a functional ATP-binding cassette, sub-family A, member 4 (ABCA4), there is an elevation of all- trans -retinal and prolonged buildup of all- trans -retinal adducts, resulting in a retinal degenerative disease known as Stargardt-1 disease. Even in this monogenic disorder, there is significant heterogeneity in the time to onset of symptoms among patients. Using a combination of molecular techniques, we studied Abca4 knockout (simulating human noncoding disease variants) and Abca4 knock-in mice (simulating human misfolded, catalytically inactive protein variants), which serve as models for Stargardt-1 disease. We compared the two strains to ascertain whether they exhibit differential responses to agents that affect cytokine signaling and/or ceramide metabolism, as alterations in either of these pathways can exacerbate retinal degenerative phenotypes. We found different degrees of responsiveness to maraviroc, a known immunomodulatory CCR5 antagonist, and to the ceramide-lowering agent AdipoRon, an agonist of the ADIPOR1 and ADIPOR2 receptors. The two strains also display different degrees of transcriptional deviation from matched WT controls. Our phenotypic comparison of the two distinct Abca4 mutant-mouse models sheds light on potential therapeutic avenues previously unexplored in the treatment of Stargardt disease and provides a surrogate assay for assessing the effectiveness for genome editing.

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Microglia at Sites of Atrophy Restrict the Progression of Retinal Degeneration via Galectin-3 and Trem2 Interactions

Cited by 3 publications

References 92 publications

Macrophages protect against sensory axon degeneration in diabetic neuropathy

Macrophages protect against sensory axon degeneration in diabetic neuropathy

Macrophages protect against sensory axon degeneration in diabetic neuropathy

Distinct mouse models of Stargardt disease display differences in pharmacological targeting of ceramides and inflammatory responses

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