In summary, these studies reveal that in male mice, non-neuronal and potentially neuronal NLRP3 are required for maintenance of postoperative inflammation and mechanical hypersensitivity, and that upregulation of NLRP3 may drive mechanical hypersensitivity through sensitization of TRPA1. By contrast, in females, most postoperative edema is independent of NLRP3, and only NLRP3 expressed in sensory neurons contributes to the postoperative mechanical hypersensitivity. The postoperative mechanical hypersensitivity in females is predominately driven independent of NLRP3 (Fig. 12).
In this study, we demonstrate that in males, maintenance (POD4) of postoperative IL-1β production is predominately due to the activation of NLRP3 in non-neuronal cells and potentially sensory neurons. NLRP3 expression induces postoperative mechanical hypersensitivity and increases the number of TRPA1-sensitive neurons. However, in females, only NLRP3 that may be expressed in sensory neurons contributes to postoperative mechanical hypersensitivity. The contributions of non-neuronal cells to postoperative mechanical hypersensitivity are independent of NLRP3. This suggests that additional inflammasomes, or inflammasome-independent IL-1β production, contribute to the postoperative mechanical hypersensitivity in females.
In males, dermal mast cells regulate inflammation immediately after cutaneous wounding by releasing inflammatory mediators, increasing vascular permeability, and recruiting neutrophils.87,137 Neutrophil recruitment is generally followed by macrophage recruitment, which occurs 1 to 2 days after injury.29,36,114 Additional support for this non-neuronal NLRP3 time course comes from studies in which mast cells92,142 and neutrophils17,122 were demonstrated to contribute to mechanical hypersensitivity for only 2 to 24 hours after surgery and studies where macrophages (indirectly) sustain the mechanical hypersensitivity after incision (ie, 24-48 hours).43 Therefore, the immediate attenuation of mechanical pain observed in NLRP3KO males, but not females, may be a result of the loss of NLRP3 in mast cells and neutrophils while the loss of NLRP3 in macrophages and sensory neurons may drive the maintenance of attenuation (POD3 and later).
In females, mast cell, neutrophil, and macrophage recruitment is like that of males where there is increased immune infiltration in the same sequence after injury. However, the extent of infiltration and inflammation patterns differ in females. After cutaneous injury, mast cells release less histamine2 and as a result a lower number of neutrophils are recruited to the site of injury in females, perhaps through the suppressive effects of estrogen.11 Similarly, Price et al. recently showed that a reduced number of macrophages are recruited to postoperative injury sites in female mice (Price, T.J., Ph.D., written personal communication, March 2018; abstract Ref. 58). Here, we show that females have less immune cell infiltration of the surgical site than males. In addition to decreased innate immune cell recruitment in females after injury, high levels of estrogen found in females skew macrophages towards the M2 phenotype (anti-inflammatory) while high levels of testosterone found in males promote the M1 phenotype (proinflammatory). In males, macrophages have higher expression of TLR4, the signal that is upstream to activation of NLRP3.63,71,81 Furthermore, sex-dependent alterations in inflammasome expression may account for the differences between the NLRP3KO males and females. Studies on the effects of sex hormones on inflammasome expression are emerging and demonstrate that high levels of estrogen attenuate NLRP3 expression and function after injury.24,148 Although females experience lower immune cell infiltration than males, elevated cytokine levels are sustained longer than males in response to injury, which may compensate for the lower immune cell infiltration.11 Furthermore, it is known that females have more tissue-resident immune cells. Therefore, males may require more recruitment of immune cells in response to injury to mount the same immune response.63 Overall, the reduced efficacy of global NLRP3 deletion for postoperative mechanical hypersensitivity in females may result from high levels of estrogen and sexual dimorphism in the innate immune system.
Global deletion of NLRP3 prevents the maintenance of postoperative pain in males, which may be a consequence of reduced peri-incisional IL-1β. General blockade of IL-1β signaling, like that obtained with FDA-approved Anakinra (IL-1 receptor antagonist), increases infections due to the necessity of IL-1β for bacterial infection clearance.15,110 Therefore, reduction of IL-1β, but not complete loss, through inhibition of NLRP3 may avoid these complications while decreasing mechanical pain. We show for the first time that sexual dimorphism exists in postoperative pain, and that it is most likely mediated by differences in male and female immune systems. An extensive study is needed to fully elucidate the inflammatory mechanisms that drive male and female postoperative pain. Overall, our study demonstrates a crucial role for NLRP3 in postoperative mechanical pain and, given the negative side effects of current postoperative therapeutics like opioids, provides a rationale for the use of NLRP3 inhibitors in male patients after surgery.
The authors have no conflicts of interest to declare.
The authors thank Dr. Bonnie Dittel, Dr. Katelyn Sadler, Dr. Jessica Ross, and Dr. Francie Moehring for editing and providing advice on organization of the manuscript. The authors thank Dr. Aniko Szabo, Director of the Medical College of Wisconsin Biostatistics Consulting Service, for advice and assistance with statistical analysis throughout the manuscript. The authors also thank the Medical College of Wisconsin Histology Core for tissue sectioning and staining and the Medical College of Wisconsin Imaging Core for slide scanning. The authors thank Neil Smith for production and design of the diagram in Figure 12.
This work was supported by the National Institute of Neurological Disorders and Stroke grants NS040538 and NS070711 to C.L. Stucky and F31GM123778 to A.M. Cowie. The Research and Education Component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin provided partial support.
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