NAAA-regulated lipid signaling in monocyte-derived cells controls the induction of hyperalgesic priming

Abstract Circulating monocytes and tissue-resident macrophages contribute in important ways to the transition from acute to chronic pain but the molecular events that cause their deployment are still unclear. Using a mouse model of hyperalgesic priming (HP), we show now that monocyte-derived cells enable the progression to pain chronicity through a cell-autonomous mechanism that requires the transient activation of the intracellular lipid hydrolase, N-acylethanolamine acid amidase (NAAA), and the consequent suppression of NAAA-regulated lipid signaling at peroxisome proliferator-activated receptor-α (PPAR-α). Inhibiting peripheral NAAA in the 72 hours following administration of one of three different priming stimuli (interleukin-6, tumor necrosis factor-α, or carrageenan), but not before or after this time interval, prevented the emergence of HP in male and female mice. This effect was phenocopied by global NAAA deletion and depended on the recruitment of PPAR-α by endogenous NAAA substrates. Transgenic mice selectively lacking NAAA in CD11b+ myeloid cells – which include monocytes, macrophages, and neutrophils – were resistant to HP induction. Conversely, mice overexpressing NAAA or lacking PPAR-α in the same cells were constitutively primed. In vivo ablation of monocytes, but not neutrophils, by administration of clodronate liposomes or blockade of type-1 colony-stimulating factor receptors, generated mice that were refractory to priming. The results identify NAAA-regulated lipid signaling in monocyte-derived cells as a control node in the induction of HP and the transition to pain chronicity.