Faculty Collaboration Database

NOD-like receptor protein 3 inflammasome drives postoperative mechanical pain in a sex-dependent manner. Pain 2019 Aug;160(8):1794-1816

Date

07/25/2019

Pubmed ID

31335648

Pubmed Central ID

PMC6662742

DOI

10.1097/j.pain.0000000000001555

Scopus ID

2-s2.0-85069147648 (requires institutional sign-in at Scopus site)   35 Citations

Abstract

Postoperative pain management continues to be suboptimal because of the lack of effective nonopioid therapies and absence of understanding of sex-driven differences. Here, we asked how the NLRP3 inflammasome contributes to postoperative pain. Inflammasomes are mediators of the innate immune system that are responsible for activation and secretion of IL-1β upon stimulation by specific molecular signals. Peripheral IL-1β is known to contribute to the mechanical sensitization induced by surgical incision. However, it is not known which inflammasome mediates the IL-1β release after surgical incision. Among the 9 known inflammasomes, the NLRP3 inflammasome is ideally positioned to drive postoperative pain through IL-1β production because NLRP3 can be activated by factors that are released by incision. Here, we show that male mice that lack NLRP3 (NLRP3) recover from surgery-induced behavioral and neuronal mechanical sensitization faster and display less surgical site inflammation than mice expressing NLRP3 (wild-type). By contrast, female NLRP3 mice exhibit minimal attenuation of the postoperative mechanical hypersensitivity and no change in postoperative inflammation compared with wild-type controls. Sensory neuron-specific deletion of NLRP3 revealed that in males, NLRP3 expressed in non-neuronal cells and potentially sensory neurons drives postoperative pain. However, in females, only the NLRP3 that may be expressed in sensory neurons contributes to postoperative pain where the non-neuronal cell contribution is NLRP3 independent. This is the first evidence of a key role for NLRP3 in postoperative pain and reveals immune-mediated sex differences in postoperative pain.

Author List

Cowie AM, Menzel AD, O'Hara C, Lawlor MW, Stucky CL

Authors

Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of Wisconsin
Cheryl L. Stucky PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Behavior, Animal
Female
Inflammasomes
Inflammation
Male
Mice
Mice, Knockout
Pain Threshold
Pain, Postoperative
Physical Stimulation
Receptors, Cell Surface
Sex Factors