# Skin Barrier Function: The Interplay of Physical, Chemical, and Immunologic Properties
## 2 The Roles of Acid, Sphingolipids, and Mitochondria in the Skin Barrier  
The epidermis, the outer layer of the skin, acts as a key permeability barrier. It continuously renews itself, requiring strict regulation of proliferation and differentiation. The skin barrier function relies greatly on a variety of variables including the stratum corneum (SC), tight junctions, and immunologic surveillance by Langerhans cells. In 1928, Dr. [PERSON] first proposed the term \"acid mantle\" to describe the inherent acidic nature of the SC [11]. Under physiological conditions, the human skin is covered with a very thin layer of acid, rendering an acidic skin pH, while the internal body maintains a near-neutral pH [12; 13]. This acidic pH of the skin influences the antimicrobial defense, barrier homeostasis, SC integrity, and function of several enzymes that are involved in synthesis and the maintenance of a healthy skin barrier. However, there are \"physiologic gaps\" in the epidermal acid barrier depending on factors that modify skin pH including the anatomical site, phototype, and age. For instance, intertriginous areas, lighter phototypes, and the skin of newborns and the elderly have a more alkaline pH [13; 14; 15]. This can disturb barrier function and favor colonization by pathogenic flora such as _S. aureus_ and _C. albicans_[13; 16; 17]. Many factors contribute to the formation of this acid mantle. The activity of the sodium-hydrogen exchanger isoform-1 protein (NHE1) directly increases the proton concentration of the stratum corneum [18]. Other acidic factors, such as lactate and free fatty acids converted from phospholipids by secretory phospholipase A2 contribute to acidity [19; 20]. It has also been proposed that filaggrin degradation products such as urocanic acid and pyrrolidine carboxylic acid contribute to skin acidity. Some studies have proposed that urocanic acid is responsible for the acid mantle of the skin, although this point has been contested [21; 22; 23]. Meanwhile, pyrrolidine carboxylic acid could also provide natural motivarizing factors in addition to its inherent acidity, further contributing to skin barrier protection [24; 25; 26; 27]. Skin pH influences the bacterial flora of the skin. A normal skin flora includes coagulase-negative staphylococci that grow at an acidic pH. Concomitant, commensal bacteria on the epidermis along with a healthy skin barrier favor a low pH and the tonic secretion of defensive mediators such as IL-12, while an impaired barrier leads to an elevated pH. Conversely, pathogenic microorganisms such as _S. aureus_ grow optimally at a neutral pH, which is clinically significant, as colonization with _S. aureus_ is associated with atopic dermatitis and subsequent dysregulation of the skin barrier [12; 13]. Alkaline pH could also contribute to the antibiotic resistance of methicillin-resistant _Staphylococcus aureus_ (MRSA) to certain beta-lactams, as culture and phagolysosome studies have shown that pH \(<\) 5.5 promotes susceptibility to meropenem and cloxacillin in MRSA [28]. Additionally, when the skin is repetitively washed with alkaline soaps, there is a rise in the pH that favors the increase in the population of _C. acnes_ and _S. aureus_[12; 13]. Alterations in skin surface pH also influence enzymatic activity. An elevated pH is known to increase the activity of serine proteases including kallikrein 5 and kallikrein 7, which cause cytokine activation and inflammation, potentially through the protease-activated receptor 2-thymic stromal lymphopoetin pathway [29; 30]. These enzymes contribute to the desquamation and degradation of corneodesmosomes by degrading desmoglen 1 [13; 31], which leads to reduced SC cohesion, which is associated with decreased lamellar body secretion [13; 32; 33; 34]. The loss of kallikrein inhibition via decreases in serine protease inhibitor Kazal type-5 (SPINK5) leads to Netherton syndrome, in which patients demonstrate impaired barrier function with epidermal hyperplasia and symptoms of atopic dermatitis [35].