Studies in rats and humans implicate CXCL5 in the mechanism causing pain hypersensitivity due to sunburn.
Scientists have used the pain sensitizing effects of UVB skin irradiation to identify the chemokine CXCL5 as a new potential target for future treatments against pain associated with inflammatory conditions such as arthritis. The team at Kings College, London evaluated changes in the gene-expression profiles of inflammatory mediators in the skin of rats and humans subjected to UVB irradiation.
The studies, reported in Science Translational Medicine, confirmed that the expression of a number of genes previously shown to contribute to pain hypersensitivity was increased in areas of skin subjected to UVB exposure. They also found that the gene transcription of a number of chemokines not previously associated with pain mechanisms were also upregulated. Of these, CXCL5 was found to be upregulated to the greatest degree in irradiated human and at skin.
Significantly, the researchers showed that injecting CXCL5 into the skin of normal, unirradiated rats resulted in similar mechanical hypersensitivity to that caused by UVB irradiation and triggered infiltration of neutrophils and macrophages into the dermis. Neutralizing the administered CXCL5 using an antibody stopped the abnormal pain-like behavior in these animals. The researchers describe their studies in a paper titled “UVB Irradiation as a Translational Pain Model Reveals CXCL5 as a Pain Mediator.”
To try and further understand the mechanisms underlying inflammatory pain, the researchers used UVB irradiation as a stimulus to compare mediator expression in human and rat skin and to identify peripheral mediators of hyperalgesia. Using custom-made PCR assays, the team measured transcripts from over 90 different putative inflammatory mediators (primarily cytokines and chemokines) at the peak of pain-related hypersensitivity in human and rat UVB-irradiated skin. Wherever possible, rat and human orthologs of the mediators were included to enable direct comparison between species.
The researchers homed in on the chemokine CXCL5, which represented the most up-regulated transcript in both species. Interestingly, the team notes, CxCL5 has not previously been implicated in nociceptive processing but is elevated in certain chronic pain syndromes. Corresponding with upregulated expression of the CXCL5 gene after UVB irradiation, levels of the protein were also significantly increased in areas of inflamed skin.
UVB-induced hypersensitivity is known to be susceptible to NSAID treatment, and in the rat UVB model administration of the NSAID drug piroxicam significantly attenuated the increased CXCL5 expression, supporting a putative role for CXCL5 in the UVB-related pain pathway.
The next step was thus to evaluate the potential pain-producing (algogenic) role of CXCL5. When the researchers administered normal rats with intraplantar injections of CXCL5, the animals demonstrated dose-dependent reductions in mechanical pain thresholds within half an hour, with these thresholds returning to baseline within 24 hours.
Interestingly, injection of the chemokine was associated with infiltration of both monocytes and polymorphonuclear (PMN) cells within the dermis six hours after injection. Conversely, while UVB-irradiated rats demonstrated reductions in mechanical withdrawal thresholds, this hypersensitivity to pain could be dampened by treatment with injections of a CXCL5 neutralizing antibody.
“Our data on UVB-induced mechanical hypersensitivity points to a previously unrecognized role for the chemokine CXCL5,” the authors note. CXCL5 has previously been shown to be involved in the recruitment and activation of leukocytes during inflammatory conditions such as arthritis.
Moreover, the researchers add, a number of the other transcripts that were significantly upregulated following UVB irradiation have also not previously been described as potential pain mediators. These include the chemokines CCL4, CCL7, CCL11, CXCL2 and CXCL7, as well as the cytokine IL-24. “The chemokine family has more than 50 members, and our data support the notion that this family contains a relatively unexplored group of promising pain mediators,” they suggest.
The degree of correlation in gene-expression changes between humans and rats subjected to UVB irradiation in addition supports the notion that the two species undergo a similar underlying biological response, at least in terms of inflammatory mediators. If other persistent pain states in humans are also found to share mechanisms with rodents, it may facilitate the development of new treatments.