NAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice.
Yannick FotioAlex Mabou TagneErica SquireHye-Lim LeeConnor M PhillipsKayla ChangFaizy AhmedAndrew S GreenbergS Armando VillaltaVanessa M ScarfoneGilberto SpadoniMarco MorDaniele PiomelliPublished in: Nature communications (2024)
Circulating monocytes participate in pain chronification but the molecular events that cause their deployment are unclear. Using a mouse model of hyperalgesic priming (HP), we show that monocytes enable progression to pain chronicity through a mechanism that requires transient activation of the hydrolase, N-acylethanolamine acid amidase (NAAA), and the consequent suppression of NAAA-regulated lipid signaling at peroxisome proliferator-activated receptor-α (PPAR-α). Inhibiting NAAA in the 72 hours following administration of a priming stimulus prevented HP. This effect was phenocopied by NAAA deletion and depended on PPAR-α recruitment. Mice lacking NAAA in CD11b + cells - monocytes, macrophages, and neutrophils - were resistant to HP induction. Conversely, mice overexpressing NAAA or lacking PPAR-α in the same cells were constitutively primed. Depletion of monocytes, but not resident macrophages, generated mice that were refractory to HP. The results identify NAAA-regulated signaling in monocytes as a control node in the induction of HP and, potentially, the transition to pain chronicity.
Keyphrases
- dendritic cells
- high fat diet induced
- chronic pain
- peripheral blood
- insulin resistance
- mouse model
- pain management
- fatty acid
- transcription factor
- neuropathic pain
- induced apoptosis
- lymph node
- type diabetes
- patient safety
- spinal cord injury
- wild type
- metabolic syndrome
- adipose tissue
- quality improvement
- postoperative pain
- skeletal muscle