Three endogenous mechanisms have emerged as potential candidates to acidify either whole stratum corneum (SC) or pH within more localized membrane domains: a) free fatty acid (FFA) generation from phospholipid (PL) hydrolysis, b) a non-energy-dependent sodium/proton membrane antiporter, NHE1, and c) urocanic acid (UCA) generation from histidine. By regulating pH, these mechanisms could regulate three key SC functions. The importance of pH for permeability barrier homeostasis is suggested by the delay in barrier recovery that occurs when perturbed skin is exposed to a neutral pH. pH could influence barrier function through regulation of extracellular lipid processing, because two of the hydrolytic enzymes exhibit acidic pH optima (b-glucocerebrosidase and acid sphingomyelinase), while two others (group 1 secretory phospholipase A2 and steroid sulfatase), display neutral-to-alkaline pH optima. Integrity/cohesion, which is inversely related to desquamation, represents a second possible pH-dependent SC function, regulated by two serine proteases: the SC chymotryptic (SCCE) and tryptic (SCTE) enzymes. Since SCCE and SCTE exhibit neutral-to-alkaline pH optima, they are likely to be active in the lower SC (=stratum compactum), and they probably increase in pathological skin, which is characterized by increased pH. Finally, an acidic SC pH could also restrict cutaneous inflammation. The SC contains precursors of both IL-la and IL-lb, which generate their active pro-inflammatory products in response to a variety of external perturbations also potentially mediated by SCCE. Consistent with this hypothesis, the pH of dermatitic (inflamed) skin of all types is typically about one unit higher than the pH of normal SC. In this proposal, we will explore the pH-dependent processes that regulate all three of these key SC functions. We will use a k.o. mutant, and inhibitor-based models, and combinations thereof, to delineate the role of each pathway in SC acidification. Then, we will explore how such pathway influence the three key functions. The information from these studies could lead to entirely new approaches to the therapy of common skin disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR019098-28
Application #
6665200
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Moshell, Alan N
Project Start
1979-04-01
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
28
Fiscal Year
2003
Total Cost
$367,388
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Hu, Lizhi; Mauro, Theodora M; Dang, Erle et al. (2017) Epidermal Dysfunction Leads to an Age-Associated Increase in Levels of Serum Inflammatory Cytokines. J Invest Dermatol 137:1277-1285
Man, George; Mauro, Theodora M; Zhai, Yongjiao et al. (2015) Topical hesperidin enhances epidermal function in an aged murine model. J Invest Dermatol 135:1184-1187
Elias, Peter M (2015) Stratum corneum acidification: how and why? Exp Dermatol 24:179-80
Man, George; Mauro, Theodora M; Kim, Peggy L et al. (2014) Topical hesperidin prevents glucocorticoid-induced abnormalities in epidermal barrier function in murine skin. Exp Dermatol 23:645-51
Man, Mao-Qiang; Lin, Tzu-Kai; Santiago, Juan L et al. (2014) Basis for enhanced barrier function of pigmented skin. J Invest Dermatol 134:2399-2407
Elias, Peter M; Gruber, Robert; Crumrine, Debra et al. (2014) Formation and functions of the corneocyte lipid envelope (CLE). Biochim Biophys Acta 1841:314-8
Elias, Peter M; Wakefield, Joan S (2014) Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis. J Allergy Clin Immunol 134:781-791.e1
Lin, Tzu-Kai; Man, Mao-Qiang; Santiago, Juan-Luis et al. (2014) Paradoxical benefits of psychological stress in inflammatory dermatoses models are glucocorticoid mediated. J Invest Dermatol 134:2890-2897
Ye, Li; Lv, Chengzhi; Man, George et al. (2014) Abnormal epidermal barrier recovery in uninvolved skin supports the notion of an epidermal pathogenesis of psoriasis. J Invest Dermatol 134:2843-2846
Elias, Peter M (2014) Lipid abnormalities and lipid-based repair strategies in atopic dermatitis. Biochim Biophys Acta 1841:323-30

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