@article {3187108,
	title = {Targeting CNS myeloid infiltrates provides neuroprotection in a progressive multiple sclerosis model},
	journal = {Brain Behav Immun},
	volume = {122},
	year = {2024},
	month = {2024 Nov},
	pages = {497-509},
	abstract = {<p>
	Demyelination and axonal injury in chronic-progressive Multiple Sclerosis (MS) are presumed to be driven by a neurotoxic bystander effect of meningeal-based myeloid infiltrates. There is an unmet clinical need to attenuate disease progression in such forms of CNS-compartmentalized MS. The failure of systemic immune suppressive treatments has highlighted the need for neuroprotective and repair-inducing strategies. Here, we examined whether direct targeting of CNS myeloid cells and modulating their toxicity may prevent irreversible tissue injury in chronic immune-mediated demyelinating disease. To that end, we utilized the experimental autoimmune encephalomyelitis (EAE) model in Biozzi mice, a clinically relevant MS model. We continuously delivered intracerebroventricularly (ICV) a retinoic acid receptor alpha agonist (RARα), as a potent regulator of myeloid cells, in the chronic phase of EAE. We assessed disease severity and performed pathological evaluations, functional analyses of immune cells, and single-cell RNA sequencing on isolated spinal CD11b+\&nbsp;cells. Although initiating treatment in the chronic phase of the disease, the RARα agonist successfully improved clinical outcomes and prevented axonal loss. ICV RARα agonist treatment inhibited pro-inflammatory pathways and shifted CNS myeloid cells toward neuroprotective phenotypes without affecting peripheral infiltrating myeloid cell phenotypes, or peripheral immunity. The treatment regulated cell-death pathways across multiple myeloid cell populations and suppressed apoptosis, resulting in paradoxically marked increased neuroinflammatory infiltrates, consisting mainly of microglia and CNS / border-associated macrophages. This work establishes the notion of bystander neurotoxicity by CNS immune infiltrates in chronic demyelinating disease. Furthermore, it shows that targeting compartmentalized neuroinflammation by selective regulation of CNS myeloid cell toxicity and survival reduces irreversible tissue injury, and may serve as a novel disease-modifying approach.
</p>
},
	keywords = {Animals, Central Nervous System, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Female, Mice, Mice, Inbred C57BL, multiple sclerosis, Multiple Sclerosis, Chronic Progressive, Myeloid Cells, Neuroprotection, Neuroprotective Agents, Retinoic Acid Receptor alpha},
	issn = {1090-2139},
	doi = {10.1016/j.bbi.2024.08.032},
	author = {Ganz, Tal and Fainstein, Nina and Theotokis, Paschalis and Elgavish, Sharona and Vardi-Yaakov, Oriya and Lachish, Marva and Sofer, Lihi and Zveik, Omri and Grigoriadis, Nikolaos and Ben-Hur, Tamir}
}
