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The immune checkpoint ligand PD-L1 has emerged as a molecular target for skin cancer therapy and might also hold promise for preventive intervention targeting solar UV light–induced skin damage. In this study, we have explored the role of PD-L1 in acute keratinocytic photodamage testing the effects of small-molecule pharmacological inhibition. Epidermal PD-L1 upregulation in response to chronic photodamage was established using immunohistochemical and proteomic analyses of a human skin cohort, consistent with earlier observations that PD-L1 is upregulated in cutaneous squamous cell carcinoma. Topical application of the small-molecule PD-L1 inhibitor BMS-202 significantly attenuated UV-induced activator protein-1 transcriptional activity in SKH-1 bioluminescent reporter mouse skin, also confirmed in human HaCaT reporter keratinocytes. RT-qPCR analysis revealed that BMS-202 antagonized UV induction of inflammatory gene expression. Likewise, UV-induced cleavage of procaspase-3, a hallmark of acute skin photodamage, was attenuated by topical BMS-202. NanoString nCounter transcriptomic analysis confirmed downregulation of cutaneous innate immunity- and inflammation-related responses, together with upregulation of immune response pathway gene expression. Further mechanistic analysis confirmed that BMS-202 antagonizes UV-induced PD-L1 expression both at the mRNA and protein levels in SKH-1 epidermis. These data suggest that topical pharmacological PD-L1 antagonism using BMS-202 shows promise for skin protection against photodamage.

The immune checkpoint ligand PD-L1 has emerged as a molecular target for skin cancer therapy and might also hold promise for preventive intervention targeting solar UV light-induced skin damage. In this study, we have explored the role of PD-L1 in acute keratinocytic photodamage testing the effects of small-molecule pharmacological inhibition. Epidermal PD-L1 upregulation in response to chronic photodamage was established using immunohistochemical and proteomic analyses of a human skin cohort, consistent with earlier observations that PD-L1 is upregulated in cutaneous squamous cell carcinoma. Topical application of the small-molecule PD-L1 inhibitor BMS-202 significantly attenuated UV-induced activator protein-1 transcriptional activity in SKH-1 bioluminescent reporter mouse skin, also confirmed in human HaCaT reporter keratinocytes. RT-qPCR analysis revealed that BMS-202 antagonized UV induction of inflammatory gene expression. Likewise, UV-induced cleavage of procaspase-3, a hallmark of acute skin photodamage, was attenuated by topical BMS-202. NanoString nCounter transcriptomic analysis confirmed downregulation of cutaneous innate immunity- and inflammation-related responses, together with upregulation of immune response pathway gene expression. Further mechanistic analysis confirmed that BMS-202 antagonizes UV-induced PD-L1 expression both at the mRNA and protein levels in SKH-1 epidermis. These data suggest that topical pharmacological PD-L1 antagonism using BMS-202 shows promise for skin protection against photodamage., (© 2024 The Authors.)

Background To date, sulphur mustard ( SM) cutaneous toxicity has been commonly assessed on account of several animal models such as pigs and weanling pigs. Few experiments however, have been carried out on mice so far. In this study, we aimed at quantifying spontaneous wound healing processes after SM exposure on a SKH-1 mouse model through non-invasive methods over an extended period of time. Methods Animals were exposed to 10 μL net SM in a vapor cup system. Measurements of barrier function (Transepidermal water loss), elasticity, skin color exposed to SM vapors were determined by evaporimetry, cutometer and image analysis on 23 animals up to 28 days. Results were subsequently correlated with histological and biochemical analyses. Results The TEWL parameter stands as a top-ranking criterion to keep track of skin barrier restoration after SM cutaneous intoxication in our SKH-1 mouse model. The R2 and R6 elasticity parameters or L° for the skin color exhibited their ability to be restored after 28 days of SM exposure. Conclusion Our findings suggest that bio-engineering methods are eligible to evaluate new treatments on SM-induced skin SKH-1 mouse lesions, thus making an allowance for less invasive methods such as histological, genomic or proteomic approaches. [ABSTRACT FROM AUTHOR]

Summary It has previously been shown that chronic exposure to low fluences of ultraviolet B radiation reduced DNA repair capacity in mouse skin. In this study we now extend this to examine the concentration dependence and tissue dependence of this phenomenon. We found that (6–4) photoproducts were repaired considerably faster than cyclobutane dimers and that the kinetics for photoproduct removal were comparable in the dermis and epidermis. Chronic ultraviolet B irradiation significantly reduced the initial rate and extent of DNA repair. After low daily doses of ultraviolet B (6–4) photoproduct repair was most affected and after high daily doses the repair of both cyclobutane and (6–4) dimers was reduced. Whereas cyclobutane dimer repair was most affected in the dermis, reduced (6–4) photoproduct repair was observed in both tissues. The deleterious effects of chronic ultraviolet exposure were sustained for a considerable time after the chronic treatment ended. [ABSTRACT FROM AUTHOR]