Epithelial Cells: Immunological Aspects

Abstract

Far from simply representing passive targets of environmental or immunological attack, epithelial cells play an active role in the generation and expression of protective immune responses. In response to physical, chemical or microbial perturbation of the epithelial barrier, these cells provide a valid defensive line by the expression of an array of soluble mediators with direct antimicrobial and/or chemotactic activities towards distinct immune cell populations and also towards cytokines and adhesion molecules that affect their functional activation. These epithelial cell‐driven molecular events are also involved in the pathogenesis of chronic inflammatory disorders, with the amplification of the inflammatory reactions because of a sustained crosstalk with infiltrating leucocytes. In particular, T‐cell‐derived cytokines have been identified as the most effective inducers of pro‐inflammatory signals in epithelial cells, in turn responsible for further recruitment and local activation of immune cells, leading to the eventual amplification of the inflammatory reaction.

Key Concepts

  • Epithelial cells organise the physical barriers of the body, the first defensive lines against environmental, physical, chemical and microbial insults.
  • In response to any damage to the physical barriers of the body, epithelial cells display their nature of resident components of the immune system and provide a second defensive line by the release of a plethora of active mediators.
  • In genetically predisposed individuals, a defective permeability of the skin early in life leads to the penetration of environmental allergens and to the initiation of the chronic inflammatory syndrome known as atopy.
  • Loss‐of‐function mutations in the filaggrin gene are the most significant and well‐replicated risk factor for the development of atopy.
  • To adequately defend against microbial colonisation and infection, epithelial cells are endowed with the complete armamentarium of innate immune defence.
  • The epidermal growth factor receptor and its endogenous ligands provide a formidable mechanism to enhance innate immunity, while they oppose activation of adaptive immunity in epithelial cells.
  • Patients with atopic dermatitis are more susceptible to cutaneous fungal, viral and bacterial pathogens because of an articulate defect in the innate immunity mechanisms of the epithelial cell.
  • Dysregulated expression of cytokines and chemokines in skin keratinocytes leads to sustained skin infiltration and local activation of a variety of immune cell populations in chronic skin inflammatory disorders including atopic dermatitis.
  • Epithelial cells possess a number of effective regulatory mechanisms to control intensity and duration of inflammatory events.

Keywords: toll‐like receptors; antimicrobial peptides; cytokines; chemokines; keratinocytes

Figure 1. The epidermis is a stratified epithelium that undergoes continuous self‐renewal in a basal to superficial direction. It is organised into basal, spinous, granular and cornified layers that correspond to progressive stages of keratinocyte differentiation. Basal keratinocytes are columnar in shape and consist primarily of mitotically active cells, including epidermal stem cells. Terminal differentiation begins when basal cells withdraw from the cell cycle and lose their ability to adhere to the basement membrane zone. The spinous cells are polyhedral, larger and more flattened than basal cells. During keratinocyte terminal differentiation in the granular layer, the plasma membrane and cellular organelles, including the nucleus, disintegrate. At this stage, transglutaminase‐dependent cross‐linking of proteins, such as involucrin, loricrin and filaggrin, and the small proline‐rich proteins result in a tough, insoluble sac called the cornified envelope surrounding the keratin fibres in the corneocytes, the eventual constituents of the cornified layer.
Figure 2. High expression of the neutrophil chemoattractant IL‐8/CXCL8 and of the T‐cell chemokine IP‐10/CXCL10 in the psoriatic lesion. These chemokines cannot be detected in the healthy skin or in relevant levels in the lesions from atopic dermatitis patients.
Figure 3. Massive CD3+ T cell infiltrate in the upper dermis and at the interface with the epidermis of a psoriatic lesion. In the inset, negative staining of healthy skin control.
Figure 4. Epidermal keratinocytes respond to a variety of exogenous stimuli with the release of a plethora of cytokines, chemokines and antimicrobial peptides implicated in the attraction and local activation of immune cells, including polymorphonucleates (PMN), macrophages (Mφ), dendritic cells (DC) and T cells. In turn, the cytokines released at high levels by infiltrating T cells, mainly represented by IFNγ, TNFα, IL‐1, IL‐17 and IL‐22, are potent activators of keratinocyte pro‐inflammatory functions, including the expression of membrane molecules involved in the retention and activation of T cells, or in the regulation of T‐cell activation, in the epidermis.
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Pastore, Saveria, Albanesi, Cristina, and Girolomoni, Giampiero(Oct 2015) Epithelial Cells: Immunological Aspects. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001127.pub2]