Lowering relative humidity level increases epidermal protein deimination and drives human filaggrin breakdown

Abstract

Background Deimination (also known as citrullination), the conversion of arginine in a protein to citrulline, is catalyzed by a family of enzymes called peptidyl-arginine deiminases (PADs). Three PADs are expressed in the epidermis, one of their targets being filaggrin. Filaggrin plays a central role in atopic dermatitis and is a key protein for the epidermal barrier. It aggregates keratins and is cross-linked to cornified envelopes. Following its deimination, it is totally degraded to release free amino acids, contributing to the natural moisturizing factor (NMF). The mechanisms controlling this multistep catabolism in human are unknown. Objective To test whether external humidity plays a role, and investigate the molecular mechanisms involved. Methods Specimens of reconstructed human epidermis (RHEs) produced in humid or dry conditions (>95% or 30–50% relative humidity) were compared. Results RHEs produced in the dry condition presented structural changes, including a thicker stratum corneum and a larger amount of keratohyalin granules. The transepidermal water loss and the stratum corneum pH were decreased whereas the quantity of NMF was greater. This highly suggested that filaggrin proteolysis was up-regulated. The expression/activity of the proteases involved in filaggrin breakdown did not increase while PAD1 expression and the deimination rate of proteins, including filaggrin, were drastically enhanced. Partial inhibition of PADs with Cl-amidine reversed the effect of dryness on filaggrin breakdown. Conclusion These results demonstrate the importance of external humidity in the control of human filaggrin metabolism, and suggest that deimination plays a major role in this regulation.

Effect of atopic skin stressors on natural moisturizing factors and cytokines in healthy adult epidermis

“…A reduction of ambient humidity and temperature has a negative effect on the skin barrier, and corneocytes cultured in low humidity have been shown to have increased filaggrin degradation . However, in the current study, a 10‐min reduction of skin temperature to 10 °C did not influence epidermal NMF levels at 24 or 48 h. The same applied to intradermal exposure to histamine.…”

Peptidylarginine deiminases and deiminated proteins at the epidermal barrier

“…In parallel, expression of PAD1 and deimination of proteins including filaggrin in the stratum corneum were enhanced. Treatments of the reconstructed human epidermis by chloro‐amidine, a pan‐PAD inhibitor, partly reversed the effect of dryness on filaggrin degradation . Therefore, we concluded that deimination is necessary and sufficient to upregulate filaggrin degradation in human epidermis when the external humidity level decreases.…”

“…Second, it improves their degradation by bleomycin hydrolase and calpain 1, at least in vitro . Third, it controls the production of NMF amino acids and derivatives according to the external relative humidity . Indeed, in the epidermis of newborn mice, the deimination of proteins, including filaggrin, in the stratum corneum , and the degradation of filaggrin were shown to be strongly upregulated 2 hours after birth .…”

“…Similarly, the degradation of filaggrin in the epidermis of adult rats was prevented by application of occlusive patches onto their skin . Recently, we have shown that human epidermis keratinocytes also respond to a decrease in external humidity by increasing both the level of filaggrin deimination and its degradation into water binding amino acids . When reconstructed human epidermis were produced in relatively dry conditions (30%‐50% relative humidity level) as compared to the usual very humid ones (>95% relative humidity level), filaggrin expression was increased, filaggrin monomer degradation was upregulated, and the levels of urocanic acid and pyrrolidone‐5 carboxylic acid were higher.…”

Using Artificial Skin Devices as Skin Replacements: Insights into Superficial Treatment

“…The skin modulates the water content of the skin by responding to the level of hydration around it. This is achieved by varying the production of hygroscopic components in the epidermis in relation to humidity conditions . At dryer conditions, degradation of filaggrin proteins is increased to release more hygroscopic free amino acids into the skin.…”