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

Women frequently experience longer-lasting pain than men, indicating delayed pain resolution, but 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.