title: Ultraviolet radiation signaling through TLR4/MyD88 constrains DNA repair and plays a role in cutaneous immunosuppression.
abstract: UV radiation (UVR) induces DNA damage, leading to the accumulation of mutations in epidermal keratinocytes and immunosuppression, which contribute to the development of nonmelanoma skin cancer. We reported previously that the TLR4-MyD88 signaling axis is necessary for UV-induced apoptosis. In the dinitrofluorobenzene contact hypersensitivity model, UV-irradiated MyD88-deficient (MyD88(-/-)) C57BL/6 mice had intact ear swelling, exaggerated inflammation, and higher levels of dinitrofluorobenzene-specific IgG2a compared with wild-type (WT) mice. Even with normal UV-induced, dendritic cell migration, DNA damage in the local lymph nodes was less pronounced in MyD88(-/-) mice compared with WT mice. Cultured, UV-irradiated WT APCs showed cleavage (inactivation) of the DNA damage-recognition molecule PARP, whereas PARP persisted in MyD88(-/-) and TLR4(-/-) APCs. Epidermal DNA from in vivo UV-irradiated MyD88(-/-) mice had an increased resolution rate of cyclobutane pyrimidine dimers. Both in vitro treatment of MyD88(-/-) APCs with and intradermal in vivo injections of PARP inhibitor, PJ-34, caused WT-level cyclobutane pyrimidine dimer repair. Lymphoblasts deficient in DNA repair (derived from a xeroderma pigmentosum group A patient) failed to augment DNA repair after MyD88 knockdown after UVR, in contrast to lymphoblasts from a healthy control. These data suggest that interference with the TLR4/MyD88 pathway may be a useful tool in promoting DNA repair and maintaining immune responses following UVR-induced damage.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201; Department of Dermatology, University of Maryland, Baltimore, MD 21201; and.
authors.forename: Erin
authors.initials: E
authors.lastname: Harberts
authors.affiliation: Department of Dermatology, University of Maryland, Baltimore, MD 21201; and.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Dermatology, University of Maryland, Baltimore, MD 21201; and.
authors.forename: Rita
authors.initials: R
authors.lastname: Fishelevich
authors.affiliation: Department of Dermatology, University of Maryland, Baltimore, MD 21201; and.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201; Department of Dermatology, University of Maryland, Baltimore, MD 21201; and Research Service, Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201 agasp001@umaryland.edu.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Gaspari
mesh_terms: D000818:Animals; D060833:Cellular Microenvironment / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects*; D012867:Skin / Q000276:immunology* / Q000378:metabolism* / Q000528:radiation effects; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4; D011065:Poly(ADP-ribose) Polymerases