# Microglial CX3CR1 deficiency regulates the selective vulnerability of cone photoreceptors via STAT3/CCL–ACKR1 signaling in the mouse retina

## TL;DR

The study shows how a lack of CX3CR1 in microglia causes specific cone cell death in the retina through inflammation and signaling pathways, offering a potential treatment target for neurodegenerative diseases.

## Contribution

The study identifies a novel mechanism involving microglial CX3CR1 deficiency and STAT3/CCL–ACKR1 signaling in the selective vulnerability of cone photoreceptors.

## Key findings

- Microglial CX3CR1 deficiency activates STAT3 signaling, leading to proinflammatory responses in microglia and astrocytes.
- Cone photoreceptor vulnerability is mediated through CCL and ACKR1 signaling, with NF-κB upregulating ACKR1 in cones.
- Cxcl1-dominant microglia interact with astrocytes via BMP2, increasing STAT3 and chemokine production, which worsens cone loss.

## Abstract

Selective neuronal vulnerability is a common feature of neurodegenerative disorders. However, the molecular mechanisms that drive this selective vulnerability are not fully understood. Here we observed that microglial CX3CR1 interference induced proinflammatory responses in microglia and astrocytes that were correlated with the selective vulnerability of cone photoreceptors in the mouse retina. Via proteomic analysis, we identified STAT3 as a potential downstream target by which CX3CR1 mediates microglial neurotoxicity. Moreover, single-cell RNA sequencing analysis revealed that CX3CR1-deficient microglia exhibit eight distinct transcriptomic phenotypes. At the mechanistic level, our data revealed that the involvement of Tnf-dominant microglia occurred mainly via microglia‒cone interactions through CCLs and their receptor, atypical chemokine receptor 1 (Ackr1), whose expression was upregulated primarily in cones through NF-κB signaling, leading to selective cone loss. In addition, we found that Cxcl1-dominant microglia primarily communicated with astrocytes via the Bmp2–Bmpr1a/Bmpr1b pair, leading to increased STAT3 levels and, consequently, elevated CCL and CXCL production in astrocytes, which in turn contributed to further cone loss through Ackr1. Overall, our data demonstrate that microglial CX3CR1 deficiency induces selective cone cell death via activation of the STAT3/CCL–ACKR1 signaling pathway, and that targeting CX3CR1/STAT3 could represent a therapeutic strategy to reduce microglial neurotoxicity.

This study explores why certain neurons in the brain are more vulnerable in degenerative contexts such as Alzheimer’s disease. The study investigates the role of CX3CL1/CX3CR1 signaling in selective neuronal vulnerability in the retina, an extension of the brain. They found that CX3CR1 deficiency in microglia activates STAT3 signaling, triggering proinflammatory responses in both microglia and astrocytes. This neuroinflammation, mediated by chemokines such as CCL and CXCL, specifically targets cone photoreceptors primarily expressing Ackr1, leading to their selective vulnerability and loss. These findings demonstrate that the CX3CR1/STAT3 pathway is a key mechanism driving selective neuronal damage, suggesting it as a promising therapeutic target for mitigating microglia-mediated neurotoxicity in neurological disorders.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.