UV-Induced Keratin 1 Proteolysis Mediates UV-Induced Skin Damage

Abstract

Keratins play critical roles in intermediate filament formation, inflammatory responses and cellular signaling in epithelium. While keratins is a major epidermal fluorophore, the mechanisms underlying the autofluorescence (AF) of keratins and its biomedical implications have remained unknown. Our study used mouse skin as a model to study these topics,showing that UV dose-dependently induced increases in green AF at the spinous layer of the epidermis of mouse within 6 hr of the UV exposures, which may be used for non-invasive prediction of UV-induced skin damage. The UV-induced AF appears to be induced by cysteine protease-mediated keratin 1 proteolysis: 1) UV rapidly induced significant keratin 1 degradation; 2) administration of keratin 1 siRNA largely decreased the UV-induced AF; and 3) administration of E-64, a cysteine protease inhibitor, significantly attenuated the UV-induced AF and keratin 1 degradation. Our study has also suggested that the UV-induced keratin 1 proteolysis may be a novel crucial pathological factor in UV-induced skin damage, which is supported by both the findings that indicate critical biological roles of keratin 1 in epithelium and our observation that prevention of UV-induced keratin 1 proteolysis can lead to decreased UV-induced skin damage. Collectively, our study has suggested that UV-induced keratin 1 proteolysis may be a novel and valuable target for diagnosis, prevention and treatment of UV-induced skin damage.

Epidermal green autofluorescence intensity is significantly associated with the serum levels of multiple cytokines of LPS-exposed mice

“…Since the structure of the LPS-induced green AF is similar with the UV-induced green AF (13), which exhibits the characteristic polyhedral structure of the keratinocytes in Stratum Spinosum, the LPS-induced green AF could also be located in the keratinocytes in Stratum Spinosum. Because the only epidermal fluorophores 1 2 that selectively exist in the keratinocytes of Stratum Spinosum are keratin 1 and keratin 10 (8,20,26), our study has suggested that keratin 1 and/or keratin 10 are the origin of the LPS-induced increases in the epidermal green AF.…”

“…As described previously (13), the epidermal AF of the ears of the mice was imaged under a two-photon fluorescence microscope (A1 plus, Nikon Instech Co., Ltd., Tokyo, Japan), with the excitation wavelength of 488 nm and the emission wavelength of 500 -530 nm. The AF was quantified as follows: Sixteen spots with the size of approximately 100 X 100 μm 2 on the scanned images were selected randomly.…”

Green autofluorescence intensity of skin and fingernails: A novel biomarker for non-invasive evaluation of pathological state of blood vessels

“…3) Compared with Low-Risk persons -the persons with relatively mild cardiovascular diseases such as hypertension, severe cardiovascular diseases and cerebrovascular diseases such as AIS can produce significant increases in the AF intensity (3). 4) We have found that keratin 1 -a major cytoskeletal protein -is rapidly degraded by such oxidative stress generators as UV (12,13). Therefore, our green AF-based evaluation method is not merely a method of 'risk evaluation'.…”

“…Our previous studies have indicated that the increased epidermal green AF indicates the injury levels produced by oxidative stress or inflammation, instead merely a probability of injury: 1) We have found that in healthy persons (3) and normal mice that are not exposed to UV (12,13) or inflammation-inducing agents (26), the basal epidermal green AF is at very low levels. 2) Such insults as UV (12,13) and LPS (26) can dose-dependently increase the epidermal AF intensity. 3) Compared with Low-Risk persons -the persons with relatively mild cardiovascular diseases such as hypertension, severe cardiovascular diseases and cerebrovascular diseases such as AIS can produce significant increases in the AF intensity (3).…”

“…Since oxidative stress can lead to increased epidermal green AF by altering keratin 1 (12,13), the increased oxidative stress of AIS patients (2,6,23) and MI patients (1,5,11,15,24) may be responsible for the increased AF intensity. Our latest study has also indicated that inflammation can produced increased epidermal green AF intensity (26).…”