Monocyte-derived IL-10 drives sex differences in pain duration

Women frequently experience longer-lasting pain than men, indicating delayed pain resolution. While
we understand that pain can be orchestrated by the close interplay between the sensory nervous system and the
immune system, it remains unclear whether this interaction contributes to the longer duration of pain in women.
Here, we demonstrate that interleukin (IL)-10+ monocytes resolve inflammatory pain by signaling to IL-10R1+
sensory neurons in a mouse model of skin inflammation. A higher number of IL-10+ monocytes in males enables
faster resolution of inflammatory pain compared to females. In both sexes, pain resolution was impaired by
deleting Il10 from monocytes or Il10ra from sensory neurons. Similarly, in humans, men’s pain resolved faster
than women’s after traumatic injury, which was associated with higher levels of circulating monocytes and IL-10
in men. In mice, androgen signaling promotes IL-10 production by monocytes, resulting in sex differences in the
number of IL-10+ monocytes. Enhancing IL-10+ monocytes in the inflamed skin through Resolvin D1 treatment
accelerated pain resolution in both sexes of mice. Our findings uncover a novel role for peripheral IL-10+
monocytes in driving sex differences in pain resolution. These results reveal a previously underappreciated
contribution of immune cells to resolving pain and preventing the transition to chronic pain.