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

• Published in: Nature communications Vol. 14; no. 1; p. 3579
• Main Authors: Sideris-Lampretsas, George, Oggero, Silvia, Zeboudj, Lynda, Silva, Rita, Bajpai, Archana, Dharmalingam, Gopuraja, Collier, David A., Malcangio, Marzia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.06.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 14/63; 45/91; 631/378/1689/1283; 631/378/1689/2610; 631/378/2596/1953; 631/378/371; 64/110; 82/80; Alzheimer Disease - genetics; Alzheimer's disease; Animals; Arthritis; Chronic pain; Chronic Pain - genetics; Disease Models, Animal; Dorsal horn; Female; Galectin 3 - genetics; Galectin-3; Horns; Humanities and Social Sciences; Hyperalgesia - genetics; Inflammation; Inhibitors; Male; Mice; Mice, Transgenic; Microglia; multidisciplinary; Neurodegenerative diseases; Neurons; Nociception; Pain; Pain perception; Science; Science (multidisciplinary); Sensory neurons; Spinal Cord; Spinal Cord Dorsal Horn; TLR4 protein; Toll-Like Receptor 4 - genetics; Toll-like receptors; Transgenic mice
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39077-1

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.