CXCL5 Mediates UVB Irradiation–Induced Pain

The cytokine CXCL5 is a peripheral mediator of pain induced by UVB irradiation to the skin. Pinpointing the Cause of Sunburn's Pain As any summer sunbather knows, when pain persists after the immediate cause is removed, it can be debilitating and can cause delayed problems such as cancer. To better understand this undesirable form of pain, Dawes et al. examine sunburned skin, a good example of inflammatory pain. Pain caused by ultraviolet B (UVB) light–induced DNA damage, these investigators found, is caused by the cytokine CXCL5. They made sure that their results from ras apply to human skin by carefully comparing how both human and rodent skin react to UVB irradiation. UV irradiation of rat foot and human forearm skin causes increased blood flow and painful hypersensitivity to mechanical and heat-induced stimuli 40 hours later. By using a large array that detected expression of many cytokines and chemokines, the authors saw an expected up-regulation of interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2) and found that the most markedly enhanced chemokine was CXCL5—in both species. Not only was CXCL5 most elevated at the time of maximum pain, it was directly shown to be an important contributor to UVB-induced pain: Its injection alone into rat skin caused mechanical (but not thermal) hypersensitivity. CXCL5 attracted neutrophils and macrophages to the inflamed area. The final proof that CXCL5 is the key regulator for UVB-induced pain is that a neutralizing antibody to the chemokine protected against the pain and infiltration of immune cells. This fits with the known ability of CXCL5 to attract neutrophils (and as shown here macrophages) by regulating their chemotaxis. Pain is not always controlled in rodent models the same way that it is in humans. This has often prevented efficient translation of results in animal models to humans. Here, the authors guarded against this problem by showing a clear correlation of the UVB response in rat and in human skin, giving them confidence that their rat results would apply in humans. At least for inflammatory pain caused by the UVB rays of the sun, CXCL5 is an attractive target for therapeutic agents. Many persistent pain states (pain lasting for hours, days, or longer) are poorly treated because of the limitations of existing therapies. Analgesics such as nonsteroidal anti-inflammatory drugs and opioids often provide incomplete pain relief and prolonged use results in the development of severe side effects. Identification of the key mediators of various types of pain could improve such therapies. Here, we tested the hypothesis that hitherto unrecognized cytokines and chemokines might act as mediators in inflammatory pain. We used ultraviolet B (UVB) irradiation to induce persistent, abnormal sensitivity to pain in humans and rats. The expression of more than 90 different inflammatory mediators was measured in treated skin at the peak of UVB-induced hypersensitivity with custom-made polymerase chain reaction arrays. There was a significant positive correlation in the overall expression profiles between the two species. The expression of several genes [interleukin-1β (IL-1β), IL-6, and cyclooxygenase-2 (COX-2)], previously shown to contribute to pain hypersensitivity, was significantly increased after UVB exposure, and there was dysregulation of several chemokines (CCL2, CCL3, CCL4, CCL7, CCL11, CXCL1, CXCL2, CXCL4, CXCL7, and CXCL8). Among the genes measured, CXCL5 was induced to the greatest extent by UVB treatment in human skin; when injected into the skin of rats, CXCL5 recapitulated the mechanical hypersensitivity caused by UVB irradiation. This hypersensitivity was associated with the infiltration of neutrophils and macrophages into the dermis, and neutralizing the effects of CXCL5 attenuated the abnormal pain-like behavior. Our findings demonstrate that the chemokine CXCL5 is a peripheral mediator of UVB-induced inflammatory pain, likely in humans as well as rats.