The first clue came when researchers noticed higher levels of inflammation-controlling proteins in male mice during induced pain. They determined that such proteins, called IL-10, come from hormone-regulating immune cells called monocytes, which were previously thought not to be important in the nervous system. To see if monocytes were truly more active in males, the researchers removed the testes of male mice and found that IL-10 levels decreased. In the reverse, when they removed female mice’s ovaries and injected a hormone similar to testosterone, the mice’s cells produced more IL-10 and resolved pain faster.
The same pattern in IL-10 could be seen in data on men and women who suffered traumatic injuries from car accidents. That finding makes the authors hopeful that future treatments for chronic pain could attempt to increase cells’ IL-10 production. “This opens new avenues for non-opioid therapies aimed at preventing chronic pain before it is established,” said Lead Author Geoffroy Laumet in a statement.
Editor’s summary
Women experience slower pain resolution and are more susceptible to developing chronic pain; however, the underlying mechanisms are poorly understood. Using a mouse model of skin inflammation, Sim et al found that IL-10–producing monocytes signal to sensory neurons to drive faster pain resolution in males. Androgen signaling in male mice promoted accumulation of IL-10+ monocytes in the skin and pain resolution, effects that could be elicited by local treatment with the lipid mediator resolvin D1. In humans experiencing traumatic injury, pain resolved faster in men than women and was associated with higher IL-10 levels. These findings identify a role for monocytes in contributing to sex differences in pain resolution. —Claire Olingy
Abstract
Women frequently experience longer-lasting pain than men, indicating delayed pain resolution; however, the mechanisms underlying this sex difference remain unclear. Here, we show that interleukin-10+ (IL-10+) monocytes resolve inflammatory pain by signaling to IL-10R1+ sensory neurons in a mouse model of skin inflammation. Male mice exhibited faster pain resolution than females, which was associated with higher numbers of IL-10+ monocytes. In both sexes, pain resolution was impaired by deleting Il10 from monocytes or Il10ra from sensory neurons. Androgen signaling promoted IL-10 production by monocytes, driving sex differences in IL-10+ monocyte abundance. Enhancing IL-10+ monocytes with resolvin D1 accelerated pain resolution in both sexes. In humans, pain resolved faster in men than in women after traumatic injury and was associated with higher circulating monocytes and IL-10 levels in men. These findings identify a role for peripheral IL-10+ monocytes in sex-specific pain resolution and highlight immune mechanisms that may prevent chronic pain.
INTRODUCTION
Chronic pain is a prevalent health issue affecting more than 100 million individuals in the United States and incurring major health care costs. There is a distinct female predominance in most chronic pain syndromes, likely driven by slower pain resolution in women. The slower resolution of pain in women increases their risk of transitioning to chronic pain. Given the strong association between the immune system and pain, as well as sex differences in immune responses, immune mechanisms may contribute to sex differences in pain.
Nociceptive neurons are specialized peripheral sensory neurons that detect noxious, potentially tissue-damaging stimuli and relay pain signals to the central nervous system. These neurons express cytokine receptors, enabling direct communication between immune cells and these neurons. Proinflammatory cytokines such as tumor necrosis factor–α (TNFα), interleukin-1β (IL-1β), and IL-6 increase the excitability of nociceptors, thereby inducing nociception. Conversely, previous research from our group and others has highlighted IL-10 as an important antinociceptive cytokine, with its effect traditionally linked to suppression of inflammation. However, specific expression of the IL-10 receptor (IL-10R) on nociceptive neurons in mice and humans raises the possibility of direct action of IL-10 on neurons. Whether IL-10 contributes to sex differences in pain resolution remains unknown.
Here, we found that male mice resolve inflammatory pain induced by complete Freund’s adjuvant (CFA) faster than females. Using spectral flow cytometry and transgenic mouse lines, we showed that infiltrating monocytes in the inflamed skin produce IL-10, which signals to IL-10R1–expressing sensory neurons to promote pain resolution. Modulating androgen signaling through dihydrotestosterone (DHT), flutamide, or surgical interventions revealed that androgen signaling enables males to have more IL-10+ monocytes than females. Mice whose monocytes lacked IL-10 or androgen receptors (ARs) exhibited delayed pain resolution. In humans, we observed that men resolved persistent traumatic pain faster than women. Higher circulating levels of IL-10 and monocytes in men were associated with their faster pain resolution. Collectively, our findings suggest that IL-10 and monocytes contribute to sex differences.
RESULTS
Male mice resolve inflammatory pain faster than females because of elevated IL-10 signaling in skin sensory neurons. CFA induces a strong inflammatory response and persistent pain. After CFA treatment in the plantar skin, wild-type (WT) mice of both sexes developed severe mechanical hypersensitivity. In contrast, intraplantar saline injections did not trigger mechanical sensitivity (fig. S1A). In CFA-treated mice, male mice began to exhibit pain resolution 1 week after injection, whereas females continued to display pronounced pain hypersensitivity. Overall, males showed faster pain resolution than females, consistent with previous preclinical reports indicating that females experience greater and longer-lasting inflammatory pain than males. Even treating with CFA at doses adjusted to body weight, female mice exhibited prolonged mechanical hypersensitivity compared with males (fig. S1B). Notably, the degree of edema resulting from CFA-induced skin inflammation did not differ between sexes, indicating comparable levels of inflammation. Whereas the number of CD45+ immune cells in the skin markedly increased after CFA treatment, we did not observe sex differences in the number of skin CD45+ cells.
REFERENCE: Science Immunology; 20 FEB 2026; Volume 11, Issue 116