Skin-Gut-Lung Epithelial Permeability

Introduction

Childhood onset of atopic dermatitis is often followed by sequential development of food allergy, allergic rhinitis, and later asthma, a phenomenon commonly known as atopic march ( ). While the cutaneous disease process has been the subject of extensive research, the mechanism by which atopic dermatitis progresses toward gastrointestinal or airway disease remains to be elucidated. Recent findings suggest that both inherited and acquired defects at epithelial barrier surfaces permit enhanced allergen penetration, immunoglobulin E (IgE) sensitization, and systemic T helper 2 (Th2) response ( ). In addition, levels of regulatory T cells (Tregs) in the skin, gut, and lung epithelia are diminished or ineffective at modulating the inflammatory response ( ). When the barrier of the epidermal skin surface fails, there is increased epicutaneous absorption of environmental allergens and a dysregulated immune response that predisposes to development of food allergy and asthma ( ). The initial insult to the skin may explain why atopic dermatitis is often the first disease to manifest in the atopic triad ( ). The chapter will highlight functions of the epithelial permeability barrier in the skin, gastrointestinal tract, and respiratory tract, and discuss how epithelial dysfunction linking microbiome alteration and immune dysregulation can predispose to development of atopic march.

Skin permeability

The epidermal barrier is composed of the stratum corneum and tight junctions (TJs) ( ). Epidermal barrier impairment in atopic dermatitis can result from altered lipid composition, dysfunctional and decreased structural proteins, increased skin pH, and reduced skin microbiome diversity. Cutaneous permeability defects can be assessed by measuring transepidermal water loss, which correlates with disease severity ( ; ).

Lipid alterations

Ceramides, free fatty acids, and cholesterol comprise the main stratum corneum lipids, of which ceramides are the most abundant ( ). Ceramides are a critical component of the lipid matrix that aids in preventing transepidermal water loss ( ). In atopic dermatitis there is decreased total ceramide content and alteration in ceramide chain length ( ). Specifically, short-chain ceramides are increased and long-chain ceramides are diminished, disrupting structural conformation and allowing increased transepidermal water loss ( ). Studies have shown that inflammatory cytokines decrease levels of long-chain ceramides by downregulating expression of key ceramide synthesizing enzymes such as elongases (ELOVL) and ceramide synthases (CerS), which are necessary for proper lipid formation ( ).

Similarly, free fatty acid chain length also influences conformational ordering of the lipid matrix. Long-chain fatty acids help maintain stratum corneum structure, whereas short-chain fatty acids induce less densely packed hexagonal lipid organization and disrupt the typical orthorhombic organization of the lipid lattice ( ). Lipid imbalance within atopic dermatitis lesions has been shown to be caused by downregulation of elongase (ELOVL), a key enzyme in fatty acid extension, which is often a result of systemic Th2 response ( ). Atopic dermatitis lesions generated with Th2 cytokines in human skin equivalents show reduced levels of ELOVL, indicating that Th2 response may cause changes in lipid composition in atopic dermatitis ( ).

Furthermore, sebaceous lipids are secreted onto the skin surface and function to lubricate the skin, prevent dehydration, provide antimicrobial support, and deliver antioxidants in the form of vitamin E ( ). In atopic dermatitis there is a reduction in sebum content (squalene and wax esters), suggesting an association between decreased sebaceous gland activity leading to skin barrier dysfunction and increased permeability ( ).

Filaggrin deficiency

Filaggrin (FLG) is a structural protein that is fundamental in forming the cornified cell envelope and maintaining intercellular cohesion ( ). Breakdown of FLG generates alanine, pyrrolidone carboxylic acid, and urocanic acid, natural moisturizing factors that preserve hydration, lower surface pH, and contribute to skin antimicrobial defense ( ). FLG deficiency leads to increased epidermal pH, which promotes serine protease activity to degrade stratum corneum desmosomes and inhibits ceramide production ( ). Inherited loss-of-function mutation in one or both FLG alleles results in either a reduced (heterozygous) or complete absence (homozygous) of epidermal FLG ( ). In mouse models with FLG–/– genotype there is expansion of innate lymphoid cells type 2 (ILC2) in the skin and airway, leading to atopic dermatitis and pulmonary inflammation, respectively ( ). FLG expression can also be downregulated by Th2 cytokines (interleukin-4 [IL4] and IL13) and environmental factors (low humidity, ultraviolet [UV] radiation, and external irritant) ( ). Studies have shown that individuals with reduced FLG levels due to loss of function mutations exhibit early-onset atopic dermatitis that is often more persistent and closely associated with asthma and food allergy than those with normal FLG levels ( ). Fig. 15.1 illustrates physiologic alterations as a result of FLG defect.

Tight junction defects

TJs are composed of transmembrane proteins—claudins, occludins, and junctional adhesion molecules—localized to the paracellular spaces of the stratum granulosum ( ). Claudin-1 and claudin-4 are responsible for intercellular sealing and formation of the liquid-liquid interface barrier within the epidermis ( ). TJ disruption weakens barrier function by altering lipid and profilaggrin processing ( ). Allergens gain rapid entry across a disrupted TJ, engage Langerhans cells, and prime the systemic inflammatory response ( Fig. 15.2 ) ( ). Fine structures of TJs are detailed in the Chapter 11 .

Proteases

Various environmental allergens, such as house dust mite, cockroach, fungi, and pollen, contain cysteine and serine proteases ( ). The proteolytic allergens can bind protease-activated receptor on keratinocytes, triggering epidermal degradation, resulting in increased permeability and Th2-mediated inflammation ( ). Reduction in serine protease inhibitors, such as serine protease inhibitor Kazal type-5, has been shown to further enhance protease-activated pathways and contribute to disease aggravation ( ).