(214) NOD-Like Receptor Protein 3 Inflammasome Drives Postoperative Pain in a Sex-Dependent Manner

Abstract

Inflammasomes are cytosolic receptors of the innate immune system that are responsible for activation and secretion of the proinflammatory cytokine interleukin-1β (IL-1β) where IL-1β is known to cause pain by directly acting on sensory neurons. Specifically, IL-1β is known to cause peripheral sensitization to mechanical stimuli in models of inflammatory and neuropathic pain. Of the multiple inflammasomes, the NOD-like receptor protein 3 (NLRP3) inflammasome is activated by endogenous molecules that are released as a result of tissue injury and thus is ideally positioned to produce the majority of postoperative IL-1β. Therefore, we aimed to uncover the mechanism by which NLRP3 modifies postoperative pain in males and females. Male mice lacking NLRP3 recovered from incisional surgery significantly faster at the behavioral and primary afferent levels and exhibited less peri-incisional inflammation than mice expressing NLRP3 (WT). In contrast, female mice lacking NLRP3 displayed only attenuated postoperative mechanical hypersensitivity and peri-incisional inflammation was unchanged compared to WT females. Furthermore, sensory neuron-specific deletion of NLRP3 revealed that, in males, NLRP3 expressed in both sensory neurons and non-neuronal cells drives postoperative pain whereas, in females, only sensory neuron NLRP3 contributes. This is the first evidence for a direct role for NLRP3 and inflammasome-mediated sex differences in postoperative pain.