Statement 3: The acidic pH of skin plays an important role in skin barrier homeostasis, which is a key factor in AD.
SC surface pH can be measured by documenting pH and buffer capacity of the skin; it is normally acidic (4.0–6.0).17 The skin barrier protects against environmental stimuli by preventing their influx, including when failing inflammatory responses to the infiltrating stimuli follow.11 Defects in this complex regulation system may lead to the loss of epithelial homeostasis, inflammation, and the development of AD. Elevated pH in the epidermis (pH around 6.5 in patients with AD compared to a pH of approximately 4.5 in those with healthy skin) leads to increased catalytic activity of proteases kallikrein 5 and 7 (KLK5 and KLK7).11 Furthermore, a decrease in the basal expression rate of LEKTI, a KLK inhibitor, leads to compromised inhibition of KLK activity.11
Statement 4: Filaggrin and its degradation are essential for maintaining the acidic pH of the skin.
Skin barrier function is dependent on the complex interplay of filaggrin, pH-dependent lipid processing enzymes, serine proteases and the skin microbiome.6,10,14-18 A further cohesive force holding corneocytes together is ‘modified desmosomes’, referred to as corneodesmosomes, which also provide tensile strength to skin barrier.6,18,19 Corneocytes are held together by corneodesmosomes, and contain NMF derived from pro-filaggrin, which are a mix of hygroscopic compounds that help maintain skin hydration.18 The balance between the expression and activity of proteases and protease inhibitors determines the rate of corneocytes shedding, which under normal conditions takes place in the upper skin layer. The production of filaggrin into NMF acidifies the SC, supporting the pH-dependent lipid processing enzymes that produce the mortar of the brick and walls of the SC.6,10,14,19 Serine proteases, which are also pH dependent, break down corneodesmosomes in the SC6,19 while a low pH acts as an antimicrobial defense mechanism limiting bacterial colonization. If the pH is increased in healthy skin, filaggrin proteolysis supports restoring the SC to a slightly acidic pH. When fewer filaggrin metabolites are produced and the skin pH increases, serine proteases are activated, triggering an enhanced breakdown of corneodesmosomes. This cascade leads to barrier disruption, thereby decreasing the thickness and function of the skin barrier (Figure 2).6,18,19 Additionally, acidic filaggrin breakdown products decrease S. aureus growth rates.6,19
Statement 5: At an acidic pH, enzymes generate lipophilic components, which are essential to a physiologic skin barrier.
The formation of the SC barrier, specifically the generation of its lipophilic components, involves several pH-dependent enzymes.6,19 Two key lipid-processing enzymes, β-glucocerebrosidase and acidic sphingomyelinase, have pH optima of 5.6 and 4.5, respectively, and are both involved in the synthesis of ceramides. The processing of lipids secreted by lamellar bodies and formation of lamellar structures require an acidic environment; the activity of β-glucocerebrosidase is 10 times lower at pH 7.4 than at pH 5.5.6,19 Additionally, free fatty acids in the extracellular space form lamellar liquid crystals at pH values of 4.5–6.0 through partial ionization.19
Statement 6: An alkaline skin surface pH decreases: stratum corneum cohesion; immune defenses; antimicrobial defense; All of which leads to increased water loss and inflammation.
Stratum Corneum Cohesion NMF contribute significantly to the acid mantle by decreasing skin colonization by pathogens.18,19 Skin surface pH also plays a role in desquamation, permeability barrier homeostasis, and SC cohesion.18 Furthermore, an increase in SC pH can cause disruption of keratinization, degradation of corneodesmosomal adhesion proteins, and creation of a ceramide, cholesterol, and fatty acids deficiency, all leading to decreased antimicrobial function.6,10-13,18-23 The balance between the expression and activity of proteases and protease inhibitors, which is optimal at an acidic pH, influences the rate of desquamation10,13,18 Hyperkeratosis and parakeratosis of the SC occur as a result of disruption to the cornification process, triggering hyperactivity of proteases, which facilitates cleavage of corneodesmosome junctions.11,12,14 As a result, edema occurs due to damaged proteins involved in tight junctions, thereby triggering uncontrolled movement of fluids in the paracellular space.12
An elevated skin surface pH can disrupt the functioning of the epidermal barrier, which is based on ‘crosstalk’ between skin