Antihistamines and the Skin Barrier

Publication: Topical antihistamines display potent anti-inflammatory activity linked in part to enhanced permeability barrier function.
Lin TK, Man MQ, Santiago JL, Park K, Roelandt T, Oda Y, Hupe M, Crumrine D, Lee HJ, Gschwandtner M, Thyssen JP, Trullas C, Tschachler E, Feingold KR, Elias PM.
J Invest Dermatol. 2013 Feb;133(2):469-78. . Epub 2012 Sep 27.

Synopsis and Significance: Usually, antihistamines are given by mouth to reduce itch.  Although they also have potent anti-inflammatory activity in tissue culture, this has not been observed when they are taken orally.  Because we have  identified high levels of histamine receptors in the epidermis, we hypothesized that they might be more effective if administered directly to the skin. We show here that topical antihistamines not only improve skin barrier function, but they also display potent anti-inflammatory activity in mouse models of several different skin diseases, such as atopic dermatitis.  These studies could lead to a paradigm shift in the ways that antihistamines are used to treat skin disorders in the future (i.e., as topical rather than internally-administered agents).  This work was recently feature on an Allure post.

Histamine and the Skin Barrier

Allergy Magazine January 2013Publication: Histamine suppresses epidermal keratinocyte differentiation and impairs skin barrier function in a human skin model.

Gschwandtner M, Mildner M, Mlitz V, Gruber F, Eckhart L, Werfel T, Gutzmer R, Elias PM, Tschachler E.  Allergy. 2013 Jan;68(1):37-47. Epub 2012 Nov 15.

Synopsis and Significance:  Histamine is another neurotransmitter, classically associated with allergic responses. We demonstrate here that it also binds to two receptors that are present in abundance in the outer part of skin, the epidermis. While it is known to mediate  itch arising deeper in the skin, in epidermis it decreases the production of critical proteins that form the cells of the stratum corneum.  In other words, histamine is ‘bad’ for the skin’s permeability barrier, and antihistamines can improve barrier function.

What Is the Best Lotion for My Dry Skin?

The best treatment for dry skin may not be a lotion at all.  Dry skin is the result of a problem with the stratum corneum and it’s ability to hold water within the tissue.  Many times this can be the result of a deficiency in the quantity or types of lipids (fats) that the skin employs to waterproof our bodies.  In the past it could be easily said that  lotions are mostly water and they would not deliver sufficient quantities of lipid to the skin to improve its waterproofing abilities.  These lotions typically felt good when they were initially applied to the skin, but they often had the net effect of drying it out – leaving the skin drier than ever.  As the water in the lotion evaporates from the skin surface, it pulls some of the skin’s own water with it. Although lotions tended to be easier to spread over the skin, dermatologists often preferred to recommend products in a cream or ointment base, because these types of emollients would supply more of the moisture trapping lipids.

With advances in the technology of formulations, this paradigm has shifted somewhat. Currently, some lotions can be quite lipid-rich and some creams quite watery.  In addition to  the lipid content of emollients, another consideration is their pH.  The optimal pH for skin care products would be in the acid range. Yet most consumers will have little information to guide them in their choice of emollient, either in terms of its water content or its pH. A recent study by Shi and coworkers   examined the pH and water content of a number of emollients available in the US. We have summarized this information in our free booklet, Taking Good Care of Your Skin.

Ceramides and Generation of the Skin’s Barrier

cover exper dermatolPublication: Ceramides stimulate caspase-14 expression in human keratinocytes.
Jiang YJ, Kim P, Uchida Y, Elias PM, Bikle DD, Grunfeld C, Feingold KR.
Exp Dermatol. 2013 Feb;22(2):113-8. doi: 10.1111/exd.12079.

Synopsis and Significance:

Ceramides are a key family of lipids, made by the epidermis, that are  required for the normal  function of the skin’s permeability barrier.  They also serve as cellular signals to trigger epidermal differentiation, resulting in formation of the permeability barrier.

Caspase 14 is an epidermal protease that regulates key events leading to barrier formation, including the breakdown of profilaggrin to filaggrin, a step in the formation of the corneocyte (or stratum corneum cell). Here, we identify a potential ‘feed-forward’ regulatory mechanism, whereby ceramides, destined for the lipid-based water barrier, also increase caspase-14 production and thereby enhance the formation of the cells that too are critical components of the skin’s barrier.

Stress and Innate Immunity of the Skin

mole cell biol feb 2013 coverPublication: A novel role of a lipid species, sphingosine-1-phosphate, in epithelial innate immunity.
Park K, Elias PM, Shin KO, Lee YM, Hupe M, Borkowski AW, Gallo RL, Saba J, Holleran WM, Uchida Y. Mol Cell Biol. 2013 Feb;33(4):752-62. Epub 2012 Dec 10.

Synopsis and Significance: The antimicrobial peptide, LL-37, a cathelicidin, is a critical component of the skin’s innate immune defense against infectious organisms. It’s production by epidermal cells, ‘keratinocytes’, is known to be regulated by vitamin D3 through the vitamin D receptor.  Here we  identify a new signaling molecule, sphingosine-1-phospate.  It increases production of  LL-37 when the epidermis is under stress; e.g., following ultraviolet light exposure, during wound healing, or under attack by pathogenic micro-organisms. Conversely, vitamin D  does not stimulate LL-37 production when the epidermis is stressed in this manner, but only under normal, baseline conditions.  Identification of this new signaling mechanism will allow the development of new topical compounds, both synthetic and natural, that could be used to enhance epidermal innate immunity and antimicrobial defense, when the skin is under microbial attack from the outside.

Neurotransmitters and the Skin Barrier

cover exper derm sept 2012Publication: Cannabinoid receptors 1 and 2 oppositely regulate epidermal permeability barrier status and differentiation.
Roelandt T, Heughebaert C, Bredif S, Giddelo C, Baudouin C, Msika P, Roseeuw D, Uchida Y, Elias PM, Hachem JP. Exp Dermatol. 2012 Sep;21(9):688-93.

Synopsis and Significance:  Both the outer part of skin, the epidermis, and  the brain  derive from the epithelial layer that covers the outside of the  embryo during early fetal life. Likely because of this common origin, the epidermis and brain share virtually the same repertoire of ‘emotional’ neurotransmitters. It has been largely assumed that these chemicals and their receptors in the skin send messages on to the brain, but our recent research suggests instead that they function as a type of ‘brain within the skin’. In this paper we show in genetically-modified mice, that a family of ligands, called cannabinoids, after binding to one of their their specific receptors, regulate a host of critical metabolic responses that affect function of the permeability barrier of the skin.  One of the receptors, when activated, improves barrier function, while the other impairs function. What triggers this regulatory system remains to be determined.