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Psoriasis is a T helper type 17–mediated immune disease. Initial triggers that lead to T helper type 17 production and inflammatory cell recruitment into skin are being delineated. Autoantigens that stimulate T helper type 17 cells are also being identified. A new and important piece of the puzzle indicates that keratinocytes not only amplify inflammation, but that they are essential for a full-blown IL-17–mediated psoriatic phenotype in mice.
Psoriasis is a prototypical T helper type 17–mediated inflammatory disease.
Keratinocytes are central and essential players in psoriasis pathogenesis.
The role of keratinocytes in psoriasis comorbidities needs to be further investigated.
Chronic inflammatory skin diseases are thought to result from the interaction of immune and/or inflammatory cells and resident epithelial cells. Distinct T-cell subsets that migrate into skin and release specific cytokines can induce one of six major response patterns in keratinocytes (
). One recently characterized example is lichenoid inflammation, characteristic of lichen planus and cutaneous lupus, where type 1 cytokines such as IFN-γ and TNF-α induce necroptosis and apoptosis in keratinocytes, resulting in interface dermatitis (
). One of the best described types of T cell-mediated inflammation leading to a chronic inflammatory skin disease is type 17 immune-driven induction of psoriasis. Moos and colleagues (2019) now provide convincing evidence that this inflammatory cascade is critically dependent on keratinocytes (
Moos and colleagues (2019) investigated several murine models in which the IL-17 receptor component IL-17RA was deleted in distinct cell types, including T cells, neutrophils, macrophages, or keratinocytes, to determine which cell types were critical IL-17 responders in skin. Topical imiquimod was used to induce psoriasis-like inflammation in the genetically manipulated and control mice. While the imiquimod mouse model does not recapitulate all aspects of human psoriasis, it is widely used (
). Interestingly, Moos and coworkers (2019) observed that elimination of IL-17RA signaling in T cells, neutrophils, or macrophages did not significantly alter psoriasis-like inflammation in imiquimod-treated mice. In contrast, mice with a specific deletion of IL-17RA in keratinocytes were largely protected from the inflammatory response. Thus, keratinocytes are critical for developing the full-blown psoriasiform phenotype in this model.
Incorporating these recent results clarifies our concept of psoriasis pathogenesis (Figure 1). Early danger signals induce T helper type 17 (or ILC3) differentiation. These cells migrate into skin, recognize autoantigens that are presented by distinct major histocompatibility complex class I molecules (
). After IL-17 receptor ligation, keratinocytes secrete antimicrobial peptides and neutrophil-attracting chemokines (CXCL1 in mice and CXCL8 in humans). This initiates a pro-inflammatory circuit and recruits neutrophils into the epidermis. Moos and colleagues (2019) speculate that IL-22–producing cells might also depend on IL-17–induced keratinocyte signals. This might explain why therapeutic neutralization of IL-17A in psoriasis also diminishes acanthosis, which is thought to be induced by IL-21 and IL-22 rather than by IL-17A/F.
In addition to the central cascade illustrated in Figure 1, there may be other inflammatory feedback loops that enhance and/or perpetuate psoriasis-like inflammation in skin. One example may involve the IL-17 family member IL-17C, which engages IL-17RA like its sister cytokines IL-17A and IL-17F, and elicits similar intracellular signaling. Unlike IL-17A/F, IL-17C can be produced by keratinocytes after stimulation with TNF-α or toll-like receptor agonists. Neutralization of IL-17C leads to marked improvement of psoriasis-like inflammation in murine models (
), suggesting that IL-17C is indeed relevant to disease pathogenesis.
Both the vehicle used in the study by Moos and colleagues (2019) and the active compound itself (imiquimod) can trigger IL-17RA–independent inflammation. Imiquimod has been reported to trigger the inflammasome independent of toll-like receptor 7/8 ligation (
) that involve activation of the inflammasome. The net result is recruitment of innate immune cells, such as monocytes. In the study by Moos and colleagues (2019), an inflammatory infiltrate consisting mostly of monocytes could still be detected, whereas hallmarks of psoriasis, such as acanthosis and neutrophilic inflammation, were absent when keratinocytes did not have functional IL-17RA. This additionally validates the importance of IL-17A/C/F signaling via IL-17RA in keratinocytes in psoriasiform cutaneous inflammation.
Insights into the involvement of epithelial cells in IL-17–mediated inflammation help explain clinical observations made in patients with rare monogenetic diseases featuring reduction or absence of type 17 cytokine signaling, such as chronic mucocutaneous candidiasis (
). In patients with chronic mucocutaneous candidiasis, type 17 cytokine signaling is attenuated due to mutations in transcription factors STAT1 or STAT3 that are downstream of the IL-17 receptor, the existence of circulating antibodies that neutralize IL-17A/F, or mutations in IL-17RA. Patients with chronic mucocutaneous candidiasis are very susceptible to chronic and severe infections that are caused by yeasts, such as Candida species, but only at skin and mucosal surfaces and not in the circulation. This highlights the fact that, in this setting, protective IL-17RA–mediated signaling occurs in epithelial cells of the skin and gut rather than in leukocytes.
Psoriasis can be conceptualized as an exaggerated physiological response to epithelial damage or wounding, and we now know that keratinocytes are essential and central players in this response (Figure 1). Like most informative studies, the results reported by
allow for speculations and suggest new questions. Could a future therapeutic strategy aim to neutralize IL-17 signaling selectively in keratinocytes? Such an approach might obviate the worsening of inflammatory bowel disease that we occasionally observe after systemic neutralization of IL-17A or IL-17RA.
Regarding new questions, the pathogenesis of psoriasis comorbidities, such as cardiovascular disease, is not completely understood. There is evidence that neutralization of IL-17A diminishes vascular inflammation (
). Are keratinocytes (or other epithelial cells) central to, or even participants in, vascular inflammation? This might be the case if pro-inflammatory cytokines, chemokines, or growth factors such as vascular endothelial growth factor diffuse from the skin into the systemic circulation. Or, in contrast to the cutaneous hallmarks of psoriasis, do psoriasis comorbidities depend on the ability of non-epithelial cells to respond to IL-17? These and other important questions need to be answered via future studies.
Conflict of Interest
NG-S reports speaker's fees and advisory board membership of AbbVie, Novartis, UCB
KE reports speaker's fees and advisory board membership of AbbVie, Almirall, Berlin Chemie, Celgene, Galapagos, Hexal, Janssen, Leo, Lilly, Novartis, Sanofi, UCB.
IL-17 and IL-22 in immunity: driving protection and pathology.
The pathology of psoriasis strongly depends on IL-17A. Monoclonal antibodies blocking either the cytokine or its receptor are among the most efficient treatments for psoriatic patients. Keratinocytes can be activated upon exposure to IL-17A and tumor necrosis factor-α and secrete secondary cytokines and chemokines in the inflamed skin. In psoriasis and its imiquimod-induced mouse model, a strong skin infiltration of neutrophils and inflammatory monocytes can be observed. However, to date, it is not clear how exactly those cellular populations are attracted to the skin and how they contribute to the pathogenesis of the disease.