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

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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)

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.

Suggested Citation

  • George Sideris-Lampretsas & Silvia Oggero & Lynda Zeboudj & Rita Silva & Archana Bajpai & Gopuraja Dharmalingam & David A. Collier & Marzia Malcangio, 2023. "Galectin-3 activates spinal microglia to induce inflammatory nociception in wild type but not in mice modelling Alzheimer’s disease," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39077-1
    DOI: 10.1038/s41467-023-39077-1
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    References listed on IDEAS

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    1. Makoto Tsuda & Yukari Shigemoto-Mogami & Schuichi Koizumi & Akito Mizokoshi & Shinichi Kohsaka & Michael W. Salter & Kazuhide Inoue, 2003. "P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury," Nature, Nature, vol. 424(6950), pages 778-783, August.
    2. Kanchan Bisht & Kenneth A. Okojie & Kaushik Sharma & Dennis H. Lentferink & Yu-Yo Sun & Hong-Ru Chen & Joseph O. Uweru & Saipranusha Amancherla & Zainab Calcuttawala & Antony Brayan Campos-Salazar & B, 2021. "Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    3. Ana Badimon & Hayley J. Strasburger & Pinar Ayata & Xinhong Chen & Aditya Nair & Ako Ikegami & Philip Hwang & Andrew T. Chan & Steven M. Graves & Joseph O. Uweru & Carola Ledderose & Munir Gunes Kutlu, 2020. "Negative feedback control of neuronal activity by microglia," Nature, Nature, vol. 586(7829), pages 417-423, October.
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