IL-23 Enhances C-Fiber-Mediated and Blue Light-Induced Spontaneous Pain in Female Mice

Abstract

The incidence of chronic pain is especially high in women, but the underlying mechanisms remain poorly understood. Interleukin-23 (IL-23) is a pro-inflammatory cytokine and contributes to inflammatory diseases (e.g., arthritis and psoriasis) through dendritic/T cell signaling. Here we examined the IL-23 involvement in sexual dimorphism of pain, using an optogenetic approach in transgenic mice expressing channelrhodopsin-2 (ChR2) in TRPV1-positive nociceptive neurons. In situ hybridization revealed that compared to males, females had a significantly larger portion of small-sized (100-200 μm2) Trpv1+ neurons in dorsal root ganglion (DRG). Blue light stimulation of a hindpaw of transgenic mice induced intensity-dependent spontaneous pain. At the highest intensity, females showed more intense spontaneous pain than males. Intraplantar injection of IL-23 (100 ng) induced mechanical allodynia in females only but had no effects on paw edema. Furthermore, intraplantar IL-23 only potentiated blue light-induced pain in females, and intrathecal injection of IL-23 also potentiated low-dose capsaicin (500 ng) induced spontaneous pain in females but not males. IL-23 expresses in DRG macrophages of both sexes. Intrathecal injection of IL-23 induced significantly greater p38 phosphorylation (p-p38), a marker of nociceptor activation, in DRGs of female mice than male mice. In THP-1 human macrophages estrogen and chemotherapy co-application increased IL-23 secretion, and furthermore, estrogen and IL-23 co-application, but not estrogen and IL-23 alone, significantly increased IL-17A release. These findings suggest a novel role of IL-23 in macrophage signaling and female-dominant pain, including C-fiber-mediated spontaneous pain. Our study has also provided new insight into cytokine-mediated macrophage-nociceptor interactions, in a sex-dependent manner.

Intrathecal Administration of the Fat-Mass and Obesity-Associated Protein Inhibitor Mitigates Neuropathic Pain in Female Rats

“…This phenomenon was further confirmed by subsequent studies from other groups [23,24,42]. IL-23 in macrophage signaling induced significantly greater p38 phosphorylation, a marker of nociceptor activation, in DRGs of female than male mice and enhanced C-fiber-mediated and blue light-induced spontaneous pain in female, but not male, mice [19,20]. Resolvins D5 repressed neuropathic and inflammatory pain in male, but not female, mice likely through targeting immune cells (e.g., macrophages) in DRG [21].…”

“…Previous studies have demonstrated that several intracellular signals are involved in the sexual dimorphism of pain. IL-23 augmented C-fiber-mediated and blue light-induced spontaneous pain in female, but not male, mice [19,20]. Resolvins D5 repressed neuropathic and inflammatory pain in male, but not female, mice [21].…”

The Roles of Optogenetics and Technology in Neurobiology: A Review

“…In 2017, a new in-spinal optogenetics device was used for pain treatment and research ( Table 1 and Figure 3 ; Samineni et al, 2017 ; Mai et al, 2020 ). Using this device, the researchers activated the afferent nerve of trpv1-chr2 channel protein, causing pain response behavior in mice ( Jacob and Szerb, 1951 ; Zhu et al, 2020 ; Ji et al, 2021 ; Zhang et al, 2021 ). The researchers then ran a real-time comparison experiment, and the results were the same.…”

Mechanosensitive Ion Channel TMEM63A Gangs Up with Local Macrophages to Modulate Chronic Post-amputation Pain

“…Macrophages are professional phagocytes responsible for the removal of dying or dead cells and cellular debris; they are mainly derived from circulating monocytes [54]. Increasing evidence has suggested that macrophages play an essential role in the initiation, maintenance, and resolution of chronic pain, depending on the location, stage, and phase of macrophages, respectively [25,29,30,32,[55][56][57]. Furthermore, macrophages are also involved in the sex dimorphism of chronic pain through modulating the IL23/IL17A axis at the peripheral terminal ends of DRG neurons [57].…”