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bioRxiv · 10.1101/2024.07.12.603316

Local keratinocyte-nociceptor interactions enhance obesity-mediated small fiber neuropathy via NGF-TrkA-PI3K signaling axis

Koui, Y.·Song, S.·Dong, X.·Mukouyama, Y.-S.
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Abstract

The pathology of diabetic small fiber neuropathy, characterized by neuropathic pain and axon degeneration, develops locally within the skin during the stages of obesity and pre-diabetes. However, the initiation and progression of morphological and functional abnormalities in skin sensory nerves remains elusive. To address this, we utilized ear skin from mice with diet-induced obesity (DIO), the mouse models for obesity and pre-type 2 diabetes. We evaluated pain-associated wiping behavior and conducted ex vivo live Ca2+ imaging of the DIO ear skin to detect sensory hypersensitivity. Our findings reveal sensory hypersensitivity in skin nociceptive axons followed by axon degeneration. Further mechanistic analysis identified keratinocytes as a major source of nerve growth factor (NGF) in DIO skin, which locally sensitizes nociceptors through NGF-mediated signaling. Indeed, the local inactivation of NGF and its receptor TrkA-mediated downstream signaling, including the phosphoinositide 3-kinases (PI3K) pathway, suppresses sensory hypersensitivity in DIO skin. Thus, targeting these local interactions between keratinocytes and nociceptors offers a therapeutic strategy for managing neuropathic pain, avoiding the adverse effects associated with systemic interventions.

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Koui, Y., Song, S., Dong, X., Mukouyama, Y.-S.. 2024-07-16. Local keratinocyte-nociceptor interactions enhance obesity-mediated small fiber neuropathy via NGF-TrkA-PI3K signaling axis. https://doi.org/10.1101/2024.07.12.603316

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