Galectin-3 activates spinal microglia to induce inflammatory nociception in wild type but not in mice modelling Alzheimer's disease

Musculoskeletal chronic pain is prevalent in individuals with Alzheimer's disease (AD); however, it remains largely untreated in these patients, raising the possibility that pain mechanisms are perturbed. Here, we utilise the TASTPM transgenic mouse model of AD with the K/BxN serum transfer model of inflammatory arthritis. We show that in male and female WT mice, inflammatory allodynia is associated with a distinct spinal cord microglial response characterised by TLR4-driven transcriptional profile and upregulation of P2Y12. Dorsal horn nociceptive afferent terminals release the TLR4 ligand galectin-3 (Gal-3), and intrathecal injection of a Gal-3 inhibitor attenuates allodynia. In contrast, TASTPM mice show reduced inflammatory allodynia, which is not affected by the Gal-3 inhibitor and correlates with the emergence of a P2Y12(-) TLR4(-) microglia subset in the dorsal horn. We suggest that sensory neuron-derived Gal-3 promotes allodynia through the TLR4-regulated release of pro-nociceptive mediators by microglia, a process that is defective in TASTPM due to the absence of TLR4 in a microglia subset. In inflammatory arthritis, pain neurons communicate with spinal cord microglia to establish nociception. Here, the authors show that this communication is mediated by pain neurons releasing galectin-3, which activates microglia through TLR4. In a mouse model of Alzheimer's disease, pain is attenuated because microglia lack expression of TLR4.

Automated summary

This study suggests that pain attenuation in a mouse model of Alzheimer's disease may be due to the absence of TLR4 in microglia and the lack of Galectin-3 released by sensory neurons.