Crosstalk: keratinocytes and immune cells in psoriasis

In the past, psoriasis was considered a skin disease caused only by keratinocyte disorders. However, the efficacy of immunosuppressive drugs and biologics used to treat psoriasis proves that psoriasis is an immune-mediated disease. Indeed, a variety of immune cells are involved in the pathogenesis of psoriasis, including dendritic cells, Th17 cells, and resident memory T cells. Furthermore, keratinocytes play a role in the development of psoriasis as immune cells by secreting antibacterial peptides, chemokines, tumor necrosis factor-α, interleukin (IL)-36, and IL-23. These immune cells and skin cells interact and drive the aberrant differentiation and proliferation of keratinocytes. This crosstalk between keratinocytes and immune cells critical in the pathogenesis of psoriasis forms an inflammatory loop, resulting in the persistence or exacerbation of psoriasis plaques.


Introduction
Psoriasis is a chronic inflammatory skin disease clinically characterized by indurated scaly erythema and pathologically by abnormal differentiation and proliferation of keratinocytes.Therefore, in the past, psoriasis was considered a skin disease caused only by keratinocyte disorders.However, reports of psoriasis successfully treated with cyclosporine have altered our understanding of the pathogenesis of psoriasis.In addition, the efficacy of immunosuppressive drugs and biologics used to treat psoriasis proves that psoriasis is an immune-mediated disease (1,2).
To date, many studies have revealed how a variety of immune cells are involved in the pathogenesis of psoriasis.Furthermore, keratinocytes are not only the consequences of immune reactions (namely, phenotype), but also themselves play a role in the development of psoriasis as immune cells.These immune cells and keratinocytes interact, consequently driving the aberrant differentiation and proliferation of keratinocytes.
In this review article, we focus on this crosstalk mechanism and discuss its importance in the pathogenesis of psoriasis.

Pathogenic Th17 cells induced by dendritic cells
Th17 cells play a pivotal role in the pathogenesis of psoriasis.Murine studies have revealed that transforming growth factor (TFG)-b and IL-6 are required to activate a unique transcription factor known as retinoid-related orphan receptor-gt (RORgt).RORgt in association with other transcription factors, increases both IL-23R and IL-17A in Th17 cells.Subsequent exposure of IL-23 to developing Th17 cells enhances Th17 cytokines, including IL-17 (11).Human Th17 cells produce mainly IL-17A, IL-17F, and IL-22 in addition to TNF-a (12,13).Their cytokines drive keratinocytes to their aberrant differentiation and proliferation, as well as producing pro-inflammatory substances.IL-23 promotes Th17 cells to become highly pathogenic.It also regulates the development and maintenance of the Th17 population (14-16).The main source of IL-23 is thought to be inflammatory dendritic cells (DC), as described in our previous review article (16), including TNF-a and inducible nitric oxide synthase (iNOS)-producing DC (Tip-DC) and slanDC.
In addition to skin Trm cells, memory-like gdT cells (30), and skin structural cells with inflammatory memory (31, 32) could be involved in psoriasis relapse (20).
Since neutrophils and mast cells staining positive for IL-17 were identified at higher densities than IL-17 + T cells in psoriatic lesions, neutrophils and mast cells are considered other significant potential sources of IL-17A in psoriasis (36)(37)(38).However, whether these cells synthesize and secrete IL-17A or whether positive staining represents cytokine uptake has yet to be determined (11).Mashiko et al. reported that human mast cells are major IL-22 producers in patients with psoriasis (39).Further investigation is needed to elucidate the role of mast cells and neutrophils in the pathogenesis of psoriasis.
Under the condition of abundant IL-23 in psoriasis lesional skin, some macrophages may produce IL-17A, IL-22 and IFN-g in addition to TNF-a as described in our previous review article (16).

Keratinocytes
Keratinocytes also act as immune cells.Some cytokines secreted by keratinocytes, including IL-17C and IL-36, act on keratinocytes in an autocrine way (46).IL-36 cytokines, such as IL-36a/b/g, are produced by keratinocytes following stimulation by TNF-a, IL-17A, IL-22, and IL-1b.IL-36 stimulates keratinocytes to produce TNF-a and IL-17C (47,48).IL-17C is expressed by (and acts on) epithelial cells (49).Keratinocytes, the main producers of (and responders to) IL-17C in the skin, contribute to psoriatic inflammation (50-52).IL-17C has been identified as a functional regulator of the initial psoriatic cytokine network, suggesting its role during the early stages of psoriatic inflammation, or the "priming" for plaque formation (53).
Cathelicidins are a class of AMPs.LL-37, one of cathelicidins, produced by skin injury and bacterial infection, activates toll-like receptor (TLR)8 in keratinocytes and induces IL-17C through the induction of IL-36g (47).Inhibition of IL-17 results in normalization of IL-36g and IL-17C to levels associated with nonlesional skin (54).

Crosstalk: keratinocytes to immune cells
Reciprocally, keratinocytes also produce various substances that affect immune cells.In this section, we focus on these substances and their effects on immune cells (Figure 2).
In a study by Liang et al., IL-22 in conjunction with IL-17A or IL-17F synergistically induced the expression of hBD-2 and S100A9 and additively enhanced the expression of S100A7 and S100A8 in keratinocytes (68).S100A7 may also havechemotactic potential in psoriasis (15, 69).The LL-37 high expression in the psoriatic epidermis may also accelerate inflammation through its capacity to enable pDC to recognize self-DNA via TLR9 (58).These AMPs affect various immune cells resulting in triggering, sustaining, and/ or exacerbating psoriatic inflammation.

IL-23
Several reports indicate that keratinocytes produce IL-23.Moreover, immunostaining of psoriatic lesions revealed enhanced expression of IL-23 in keratinocytes (73,74).Park et al., using publicly available single-cell RNA sequencing data from human samples, revealed that IL-23 expression was detectable in psoriatic keratinocytes as well as DCs (75).Kelemen et al. reported that psoriasis-associated inflammatory conditions induced IL-23 mRNA expression in normal huma epidermal keratinocytes (76).Li et al., using a genetic mouse model, showed that keratinocyte-produced IL-23 was sufficient to cause chronic skin inflammation with an IL-17 profile and that epigenetic control of IL-23 expression in keratinocytes was important for chronic skin inflammation (77).However, whether the expression of IL-23 in keratinocytes in psoriasis contributes to the development of psoriasis remains to be elucidated.

Effect of IL-17 or IL-23 inhibition on immune cells and keratinocytes in psoriasis
As mentioned above, IL-23 and IL-17 play important roles in the pathogenesis of psoriasis.Indeed, biologics, including IL-23 inhibitors and IL-17 inhibitors, greatly impact keratinocytes and immune cells in psoriasis.
Secukinumab (an anti-IL-17 antibody) and guselkumab (an anti-IL-23 antibody) decrease the frequencies of inflammatory monocyte-like cells, inflammatory DC-like cells, and CD4 + CD49a -CD103 -T cells (78).Furthermore, bimekizumab (an anti-IL17A/F antibody) induces normalization of keratinocyterelated gene products, including CXCL1, CXCL8, CCL20, IL-36g, and IL-17C, to levels associated with non-lesional skin (54).Krueger et al. reported that secukinumab caused reductions in critical downstream targets of IL-17A in the skin, including the AMPs (DEFB4A/b-defensin 2 and the S100 family) in addition to reductions in IL-23 and IL-17 in transcriptomic analyses (79).Inhibition of IL-23 or TNF-a also caused reductions in the gene expression of Th17-induced mediators by keratinocytes, including antimicrobial peptides (80,81).Mehta et al. reported that inhibition of IL-23 reduced memory T cells while maintaining regulatory T cells, and vice versa for secukinumab (78).Furthermore, Whiley also revealed that clinical anti-IL-23 therapy depleted IL-17producing Trm cells from the skin of patients with psoriasis (82).