Sex differences in peripheral immune cell activation: Implications for pain and pain resolution

Decades of research into chronic pain has deepened our understanding of the cellular mechanisms behind this process. However, a failure to consider the biological variable of sex has limited the application of these breakthroughs into clinical application. In the present study, we investigate fundamental differences in chronic pain between male and female mice resulting from inflammatory activation of the innate immune system. We provide evidence that female mice are more sensitive to the effects of macrophages. Injecting small volumes of media conditioned by either unstimulated macrophages or macrophages stimulated by the inflammatory molecule TNFa lead to increased pain sensitivity only in females. Interestingly, we find that TNFa conditioned media leads to a more rapid resolution of mechanical hypersensitivity and altered immune cell recruitment to sites of injury. Furthermore, male and female macrophages exhibit differential polarization characteristics and motility after TNFa stimulation, as well as a different profile of cytokine secretions. Finally, we find that the X-linked gene Tlr7 is critical in the facilitating the adaptive resolution of pain in models of acute and chronic inflammation in both sexes. Altogether, these findings suggest that although the cellular mechanisms of pain resolution may differ between the sexes, the study of these differences may yield more targeted approaches with clinical applications.

Automated summary

Decades of research have enhanced our understanding of the cellular mechanisms underlying chronic pain, but the biological variable of sex has been overlooked, limiting the clinical application of these breakthroughs. This study investigates the differences in chronic pain between male and female mice resulting from inflammatory activation of the innate immune system. The findings suggest that sex differences in cellular mechanisms may lead to more targeted approaches for clinical applications.