CD47-SIRPα Axis as a Target for Neuroprotection.

Authors

Ariadna Regina Gómez-López, Gemma Manich, Clara Penas, Judit Pampalona, Nàdia Villacampa, Beatriz Almolda, Emilie Viennois, Santiago Rojas, Berta González, Bernardo Castellano

Published in

Glia. Volume 74. Issue 12. Pages e70242.

Abstract

Microglial "Off" signaling is crucial for maintaining microglia in a homeostatic state through the interaction of "Off" neuronal ligands with their corresponding microglial receptors. Dysregulation of "Off" signaling has been reported in both acute and chronic neuroinflammation; however, the influence of inflammatory mediators on this pathway remains underexplored. Here, we investigated whether chronic IL-6 or IL-10 overexpression modulates microglia-neuron "Off" signaling after FNA, thereby accounting for the previously observed differences in facial motoneuron (FMN) survival and microglial reactivity in transgenic mouse models (GFAP-IL6Tg and GFAP-IL10Tg). To this end, we examined the expression of the neuronal "Off" ligands CD200, CX3CL1, CD47, and CD22, as well as their corresponding microglial "Off" receptors CD200R, CX3CR1, SIRP-α, and CD45 in non-lesioned and axotomized GFAP-IL6Tg, GFAP-IL10Tg, and WT mice across multiple time points. Our analyses revealed the dynamic regulation of "Off" signaling in both neurons and microglia during microgliosis and FMN phagocytosis and showed temporally restricted strain-specific differences in CD47 expression across genotypes. Chronic IL-6 overproduction promoted a more phagocytic microglial phenotype, defined by downregulation of SIRPα and CX3CR1 alongside upregulated CD45 in the microglial population. In contrast, chronic IL-10 overproduction did not alter the expression of microglial "Off" receptors but induced an IL-10 dependent accelerated upregulation of neuronal CD47. Our findings highlight the CD47-SIRPα axis as a key regulator of FMN death via microglial phagocytosis and emphasize IL-10's neuroprotective potential role through enhanced neuronal CD47 signaling. Overall, this work positions the CD47-SIRPα axis as a potential therapeutic target to mitigate neuroinflammation-induced neuronal loss.

PMID:
42897749
Bibliographic data and abstract were imported from PubMed on 20 Oct 2026.

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