Role of IL-22 in homeostasis and diseases of the skin

Abstract

Interleukin-22 (IL-22) is a cytokine mainly produced by T cells and innate lymphoid cells (ILC). IL-22 primarily targets non-hematopoietic cells such as epithelial cells and fibroblasts. In the skin, IL-22 promotes the proliferation of keratinocytes and dermal fibroblasts. IL-22 furthermore regulates innate immune responses as it induces the production of antimicrobial proteins and neutrophil-attracting chemokines. IL-22 plays an important role in wound healing and in the protection against skin infections. However, IL-22 can also contribute to the pathogenesis of several inflammatory skin diseases such as psoriasis, atopic dermatitis and allergic contact dermatitis. In this review, current information regarding the structure, function and regulation of IL-22 is discussed with a special focus on the role of IL-22 in the skin and in skin diseases.

Keywords: Cytokine; IL-22 receptor; immunology; inflammatory skin diseases; interleukin-22; skin.

Fig. 1

Proposed model for IL‐22 gene regulation. Various cytokines and other factors affect il22 expression and IL‐22 secretion. Some of these factors upregulate IL‐22 levels, whereas others are seen to downregulate IL‐22. The cytokines IL‐6, TNF, IL‐1β and IL‐23 have all been shown to increase IL‐22 levels. This is possibly due to their actions in upregulating the activity of the transcription factor, RORγt, that can directly bind to the promoter region of the il22 gene and mediate transcription. Furthermore, the activity of the transcription factor, AhR, has also been found to regulate IL‐22 expression and production. Thus, ligands that bind and activate AhR (such as the AhR agonist, FICZ), lead to increased IL‐22, whereas inhibition of AhR activity (such as with the AhR antagonist, CH‐223191) leads to decreased IL‐22 levels. Additionally, vitamin A has been shown to augment IL‐22 production. Upon binding to the RAR, the complex translocates to the nucleus, where it together with RXR forms a complex that can upregulate expression of the il22 gene. Other factors inhibit IL‐22 levels. Signalling by TGFβ through the TGFβ receptor has been found to decrease IL‐22 levels. Furthermore, it has recently been shown that vitamin D₃ exerts an inhibitory effect on IL‐22. This is due to the presence of a negative vitamin D‐response element (VDRE) in the promotor‐region of the il22 gene. Upon interaction between vitamin D₃ and VDR, this complex translocates to the nucleus, where it together with RXR forms a heterodimer that can downregulate expression of the il22 gene and consequently IL‐22 secretion is inhibited. Furthermore, there is most likely also other regulatory factors of IL‐22, which is indicated by the question mark in the figure. AhR, aryl hydrocarbon receptor; ARNT, AhR nuclear translocator; RAR, retinoic acid receptor; RORγt, RAR‐related orphan receptor γ; RXR, retinoid X receptor; TGFβ, transforming growth factor β; TNF, tumor necrosis factor; VDR, vitamin D receptor.

Fig. 2

IL‐22R and its intracellular signalling. The heterodimeric IL‐22R consists of the IL‐22R1 and the IL‐10R2. When IL‐22 is not sequestered by the soluble protein, IL‐22BP, it is able to bind the IL‐22 receptor. Upon this binding, intracellular signalling is initiated, which starts with the activation of the receptor‐associated JAKs and TYKs. Activation of these kinases mediates the phosphorylation of various STAT molecules, with STAT3 phosphorylation being the most pronounced. This phosphorylation allows STAT3 to form homodimers, which can translocate to the nucleus and regulate the transcription of STAT3‐responsive genes. Furthermore, STAT1 and STAT5 molecules are also activated. IL‐22R signalling is also seen to activate the MAPK pathways involving ERK1/2, JNK and p38, as well as the PI3K‐Akt‐mTOR pathway. Akt, protein kinase B; ERK, extracellular signal‐regulated kinase; IL‐10R, IL‐10 receptor; IL‐22BP, IL‐22‐binding protein; IL‐22R, IL‐22 receptor; JAK, Janus kinases; JNK, c‐Jun N‐terminal kinase; MAPK, mitogen‐activated protein kinase; mTOR, mammalian target of rapamycin; p38, p38 mitogen‐activated protein kinase; PI3K, phosphoinositide 3‐kinase; STAT, signal transducer of activated T cells; TYK, tyrosine kinases.