Interleukin-22 and keratinocytes; pathogenic implications in skin inflammation

Interleukin (IL)-22 is produced from immune cells such as T helper (Th)22 cells, Th17/22 cells, and group 3 innate lymphoid cells. IL-22 signals via the IL-22 receptor 1 (IL-22R1) and the IL-10 receptor 2 (IL-10R2). As the IL-22R1/IL-10R2 heterodimer is preferentially expressed on border tissue between the host and the environment, IL-22 is believed to be involved in border defense. Epidermal keratinocytes are the firstline skin barrier and express IL-22R1/IL-10R2. IL-22 increases keratinocyte proliferation but inhibits differentiation. Aryl hydrocarbon receptor (AHR) is a chemical sensor and an essential transcription factor for IL-22 production. In addition, AHR also upregulates the production of barrier-related proteins such as filaggrin in keratinocytes, suggesting a pivotal role for the AHR-IL-22 axis in regulating the physiological skin barrier. Although IL-22 signatures are elevated in atopic dermatitis and psoriasis, their pathogenic and/or protective implications are not fully understood.

from specific acquired and innate hematopoietic cells, but its receptor, IL-22R1/IL-10R2, is preferentially expressed on non-hematopoietic cells such as epidermal keratinocytes [1][2][3]. Therefore, the physiological and pathological interaction between IL-22 and keratinocytes has gained particular attention from the viewpoint of skin barrier integrity and as a potential new target for the treatment of these inflammatory skin diseases [15,16].  is primarily produced by immune cells including CD4 + Th cells, CD8 + cytotoxic T (Tc) cells, natural killer T (NKT) cells, and group 3 innate lymphoid cells (ILC3) [1][2][3]. Non-lymphoid cells, including macrophages, neutrophils, mast cells, and fibroblasts may also produce IL-22, but production in keratinocytes does not occur [1-3, 15, 17]. Th and Tc cells are subdivided into several specialized subsets depending on surface markers, cytokine production and the expression of critical transcription factors as exemplified in Table 1 [18].
AHR is a chemical sensor for various endogenous and exogenous ligands and serves as a cardinal transcription factor that promotes epidermal differentiation and barrier function [35][36][37]. The skin and intestinal tract are rich in AHR ligands produced from commensal microbiomes [32,[38][39][40][41]. Ultraviolet B (UVB) ray irradiation also generates high-affinity AHR ligands from tryptophan in the skin [42]. These AHR ligands are crucial for maturation of the host immune system against symbiotic commensal microbiomes via IL-22 induction [43]. In humans, AHR agonists reduce gene expression of the Th17 master transcription factor RORC without affecting TBX21, GATA3 and FOXP3 [21]. They also decrease the expression of IL-23R [21]. Importantly, AHR ligation not only decreases the number of Th17 cells but also primes naive CD4 + T cells to produce IL-22 without affecting IL-17A or IFN-γ production, suggesting a pivotal role of AHR in developing Th22, but not Th17, cells in humans [21,31] (Figure 1). In contrast, development Tfh: T follicular helper; Tfc: T follicular cytotoxic; Treg: regulatory T; TGF: transforming growth factor of both Th17 and Th22 cells is compromised in Ahr-deficient mice [33]. The number of IL-22-expressing ILCs is also markedly decreased in Ahr-deficient mice [32]. In addition to their potent activity towards Th22prone immune deviation, AHR ligands can potentially upregulate the production of barrier-related proteins including filaggrin and loricrin, which enhance skin barrier integrity [35][36][37] (Figure 1).
It is intriguing that AHR is also an essential upstream transcription factor for IL-24 production in keratinocytes [44][45][46]. The relationship between AHR activation and IL-20 production is unknown thus far.
IL-6 plays a critical role in the expression of IL-22R1 in keratinocytes because its expression is markedly decreased in IL-6-deficint mice [71].  enhances the expression of IL-22R1 likely because it upregulates expression of the IL-6 receptor in keratinocytes [72,73].

IL-22 and keratinocyte function
Many researchers have proposed a key role for IL-22 in epithelial border patrol especially in the intestinal tract, skin and airway [16,74,75]. The intestinal tract and its commensal and pathologic microbiomes maintain a homeostatic equilibrium with regard to host defense. IL-22 stimulates epithelial cells to produce antimicrobial peptides that are synergistically or additively upregulated in the presence of IL-17A [16]. IL-22 upregulates the production of CXCL1, CXCL5, CXCL9 and IL-6, which induce recruitment of relevant innate and acquired immune cells [16] (Figure 1). In addition, IL-22 induces the production of complement 3 from hepatocytes, which facilitates neutrophil killing of invading pathogens [74,75]. Numerous AHR agonists are supplied to the intestinal tract from the diet and microbial metabolites which facilitate IL-22 production from intestinal IL-22-producing immune cells [76].
However, IL-22 exhibits a beneficial effect on tight junctions. A recent study of bronchial epithelial cells demonstrated that IL-22 has the potential to reduce inflammation during influenza infection by enhancing tight junction activity [99]. Such protective function of IL-22 on tight junctions has been shown in keratinocytes in vitro, while IL-17A significantly downregulates tight junction expression in the epidermis [100].

Conclusion
IL-22 is produced from hematopoietic cells, and its receptor, IL-22R1/IL-10R2, is expressed on keratinocytes. Ligation of IL-22R1/IL-10R2 by IL-22 generally increases proliferation and inhibits differentiation of keratinocytes. This fundamental effect of IL-22 appears to work either as a pro-or anti-inflammatory depending on the type and timing of skin inflammation involved, but the precise physiopathological roles of IL-22 in the skin are not fully understood. Recent clinical studies have revealed that excess IL-22 in lesional skin may worsen atopic dermatitis, because the anti-IL-22 antibody fezakinumab shows a therapeutic potential for treating severe atopic dermatitis patients [11,101]. Further clinical studies are necessary to explore the exact pathogenic implications of IL-22 in skin inflammation.

Conflicts of interest
The authors declare no conflicts of interest.

Ethical approval
Not applicable.