CXCL1 Inhibition Regulates UVB-Induced Skin Inflammation and Tumorigenesis in Xpa-Deficient Mice

Abstract

Xeroderma pigmentosum complementation group A is a hereditary disease characterized by early onset of skin cancers and freckle-like pigmented maculae in sun-exposed sites. Although the etiology of the predisposition to UVR-induced skin tumors in xeroderma pigmentosum complementation group A is well investigated as a repair deficiency in UVR-induced DNA damage, the mechanism of exaggerated sunburn in patients with xeroderma pigmentosum complementation group A and whether UVR-induced inflammation relates to a skin tumor-prone phenotype remains to be elucidated. Using gene profiling of xeroderma pigmentosum complementation group A model mice, Xpa-deficient mice, we found that expression of CXCL1 in the skin and blood of Xpa-deficient mice increased significantly after UVB exposure over even a limited area compared with that of wild-type mice. We administered CXCL1 neutralizing antibody or the antioxidant agent, N-acetylcysteine, to Xpa-deficient mice after UVB irradiation and found significant suppression of blood levels of CXCL1, ear swelling and erythema, the hallmarks of inflammation and neutrophil chemotaxis. Xpa-deficient mice treated with chronic UVB exposure plus administration of CXCL1 neutralizing antibody or N-acetylcysteine yielded many fewer skin tumors compared with the control group. This indicates that the UVB-induced strong inflammatory response of Xpa-deficient mice plays a role in skin tumor development, which could be suppressed by regulating chemokines such as CXCL1.

Inflammation Due to Voriconazole‐induced Photosensitivity Enhanced Skin Phototumorigenesis in Xpa‐knockout Mice

“…Mouse embryonic fibroblasts (MEFs) were prepared from E13.5 embryos of Xpa ‐knockout and wild‐type mice . The MEFs of each Xpa genotype were exposed to 0.20 kJ m −2 broadband UVB following the addition of 10 μg mL −1 voriconazole, 10 μg mL −1 voriconazole N‐oxide (VN‐oxide), or 10 ng mL −1 HCTZ in PBS and incubation until the time point of corresponding DNA isolation.…”

“…Subsequently, nonmelanoma skin cancer and melanoma may develop in the sun‐exposed area of the skin after a long‐term voriconazole administration , featuring multiple squamous cell carcinomas and their precursor lesions, actinic keratosis, distributed over the face and neck . We previously showed that UVB‐induced inflammatory response was highly associated with DNA damage caused by UVB, such as 8‐oxo‐7,8‐dihydroguanine (8‐oxoGua) and cyclobutane pyrimidine dimers (CPDs) using Ogg1 knock‐out mice or Xpa ‐knockout mice, which are deficient in repairing DNA damage, 8‐oxoGua or CPDs, respectively Namely, Ogg1 ‐knockout mice and Xpa ‐knockout mice produced more intense UV‐induced inflammatory response and expressed much higher inflammatory cytokines such as CXCL1 . The study has also shown that Ogg1 ‐knockout mice and Xpa ‐knockout mice are more susceptible to UV‐induced tumorigenesis.…”

“…The study has also shown that Ogg1 ‐knockout mice and Xpa ‐knockout mice are more susceptible to UV‐induced tumorigenesis. Furthermore, CXCL1, a neutrophil attractant chemokine, is significantly upregulated in the blood serum of Xpa‐ knockout mice after UVB exposure and once the neutralizing antibody against CXCL1 was administered at every exposure of UVB, the number of developed skin tumors in Xpa ‐knockout mice actually decreased . Long‐term use of the diuretic agent hydrochlorothiazide (HCTZ), another photosensitizing drug, was associated with an increased risk of nonmelanoma skin cancer and we previously showed that HCTZ enhanced the formation of CPD after UVA irradiation .…”

Evaluation of Acute Reactions on Mouse Skin Irradiated with 222 and 235 nm UV‐C

“…Skin specimens were fixed in 10% neutralized formalin and embedded in paraffin. Immunohistochemical staining for CPD detection was performed using a monoclonal antibody against CPD (TDM‐2 1:5,000 dilution) as described previously ( 22 ). Specimens were observed using a Biozero BZ‐X710 microscope (Keyence, Osaka, Japan).…”

>i<In vivo>/i< effects of DNA lesions in Nucleotide Excision Repair deficient mice

“…The NLRP3 inflammasome protein complex, related to IL-1α and NF-κB, has also been shown to be activated by UV-induced DNA damage (124). These proinflammatory pathways have been proposed to be a type of UV-induced DNA damage response, with NER having a major role in regulating the pathways involved in this process (222). Moreover, UV induced inflammation has also been shown to have a role in tumorigenesis alongside UV photolesions themselves (223), with the inhibition of inflammation resulting in a decrease in cancer incidence after chronic UV irradiation in both NER proficient and deficient mice (224,225).…”