Epidermal tight junctions in health and disease

Abstract

The skin, the largest organ of the body, is an essential barrier that under homeostatic conditions efficiently protects and/or minimizes damage from both environmental (e.g. microorganisms, physical trauma, ultraviolet radiation) and endogenous (e.g., cancers, inflammation) factors. This formidable barrier function resides mainly in the epidermis, a dynamic, highly-stratified epithelium. The epidermis has 2 major barrier structures: stratum corneum, the outmost layer and tight junctions, intercellular junctions that seal adjacent keratinocytes in the stratum granulosum, found below the stratum corneum. In recent years there have been significant advances in our understanding of tight junction function, composition and regulation. Herein we review what is known about tight junctions in healthy skin and keratinocyte culture systems and highlight the dynamic crosstalk observed between tight junctions and the cutaneous immune system. Finally we discuss the preliminary observations suggesting that tight junction function or protein expression may be relevant for the pathogenesis of a number of common cutaneous inflammatory and neoplastic conditions.

Keywords: AD, atopic dermatitis; AMP, antimicrobial peptides; Cldn, claudin; DC, dendritic cells; FLG, filaggrin; JAM, junctional adhesion molecule; LC, Langerhans cells; MM, malignant melanoma; PRR, pattern recognition receptor; PS, psoriasis; SCC, squamous cell carcinoma; SC, stratum corneum; SG, stratum granulosum; SNP, single nucleotide polymorphism; TER, TransEpithelial Electrical Resistance; TJ, tight junction; TLR, Toll-like receptor; Th, T helper; ZO-1, zonula occludens 1; claudins; skin barrier; skin immune system; skin innate barrier; tight junction.

Figure 1.

Representative staining of claudin-1, occludin and CD1a (LCs marker) in healthy human epidermis (whole-mount). Occludin (red),(A) staining showed a characteristic chicken wire pattern in the upper layers of human epidermis, while claudin-1 (green), (B) staining appeared less prominent (Top view). As noticeable in the side view of 3D reconstructed z-stacks, occludin expression is restricted to top stratum granulosum layers, as it can be identified with DAPI (blue-nuclear staining). Claudin-1 staining is visible from the basal layer up to stratum granulosum. Under homeostatic condition, Langerhans cells (CD1a-red); (C) bodies are located in the basal layer with the dendrites extending toward the SG (side view), (D). This can be appreciated better in the side view of merged claudin-1 and CD1a image (D) and with DAPI (E). Importantly, majority of CD1a-positive dendrites did not extend above the SG and stop at the top of claudin-1 staining. Bars: 40 μm.

Figure 2.

Representative staining of claudin-1 and ZO-1 in tumors and healthy skin sections. Staining of claudin-1 (A, C, E, G), ZO-1 (B, D, F, H) and claudin-5 (C2) in malignant melanoma (A, B), Merkel cell carcinoma (C, C2, D), squamous cell carcinoma (E, F) and healthy skin (G, H). Note the presence of ZO-1 in all 3 tumor entities (B, D, F), while Claudin-1 is absent/faintly cytoplasmic in melanoma (A), and Merkel cell carcinoma (C) and downregulated in squamous cell carcinoma (E) as compared to healthy skin (G). e: epidermis, t: tumor, Bar: 50 μm.