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

George Sideris-Lampretsas, Silvia Oggero, Lynda Zeboudj, Rita Silva, Archana Bajpai, Gopuraja Dharmalingam, David A. Collier and Marzia Malcangio ()
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George Sideris-Lampretsas: Wolfson Centre for Age-Related Diseases, King’s College London
Silvia Oggero: Wolfson Centre for Age-Related Diseases, King’s College London
Lynda Zeboudj: Wolfson Centre for Age-Related Diseases, King’s College London
Rita Silva: Wolfson Centre for Age-Related Diseases, King’s College London
Archana Bajpai: Eli Lilly & Company, Surrey, 8 Arlington Square West
Gopuraja Dharmalingam: Eli Lilly & Company, Surrey, 8 Arlington Square West
David A. Collier: Eli Lilly & Company, Surrey, 8 Arlington Square West
Marzia Malcangio: Wolfson Centre for Age-Related Diseases, King’s College London

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39077-1

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