The Biological Basis of Disease Recurrence in Psoriasis

A Historical Perspective and Current Models

Lluís Puig; Antonio Costanzo; Ernesto J. Muñoz-Elías; Maria Jazra; Sven Wegner; Carle F. Paul; Curdin Conrad

Disclosures

The British Journal of Dermatology. 2022;186(5):773-781. 

In This Article

Dendritic Cells and Mononuclear Phagocytes in Psoriasis Immunopathology

Dendritic cells (DCs) are antigen-presenting cells that can be recruited from the circulation to modulate local immune responses at sites of skin inflammation or infection;[41] Langerhans cells (LCs) are specialized DCs residing in the epidermal layer of the skin.[42,43] Martini et al.[44] demonstrated differences in the phenotypic and functional properties of epidermal DCs (eDCs) and epidermal-resident LCs in psoriasis where eDCs, which occurred only in psoriasis, were phenotypically different from normal DCs and were completely absent in resolved psoriasis. They also found that eDCs highly expressed genes involved in neutrophil recruitment and keratinocyte and T-cell activation. Additionally, while epidermal-resident LCs responded to Toll-like receptor (TLR) activation with increased IL-23 production, eDCs produced IL-23 together with IL-1β and TNF-α. This finding is further supported by a recent single-cell RNA sequencing study of all DC subsets, which found that CD14+ DCs increased in lesional skin and coproduced IL-1β and IL-23A.[45]

Nakajima et al.[46] used a transgenic mouse model of psoriasis in which Stat3 is constitutively activated in keratinocytes to investigate whether LCs are involved in the pathogenesis of psoriasis lesions. Compared with non-transgenic mice, the K5.Stat3C mice showed an increased number of LCs in skin-draining lymph nodes that preceded development of psoriasis-like lesions. Notably, psoriasis-like lesions were attenuated when LCs were depleted, suggesting a critical role for LCs in the pathogenesis of psoriasis. Additionally, LCs in the lesions of both K5.Stat3C mice and patients with psoriasis produced IL-23, which in turn induces IL-17-producing Th17 cell differentiation.

Plasmacytoid DCs (pDCs) are a unique, rare subset of DCs that are capable of secreting large amounts of type I IFNs.[47] During infection, pDCs are activated through TLR7 and TLR9 by viruses that enter the cells. Besides their critical role in antiviral immunity, type I IFNs are also implicated in numerous autoimmune diseases, as they link innate and adaptive immunity. Under physiological conditions, skin injury induces transient expression of antimicrobial peptides, which can bind and transport microbial and self nucleic acids into pDCs, enabling their activation. In psoriasis, antimicrobial peptides are overexpressed, thereby leading to prolonged pDC activation and excessive type I IFN production. Type I IFN then triggers chronic activation of dermal DCs, which produce TNF and IL-23, which in turn drive the pathogenic Th17 response. Thus, the type I IFN-driven pathway, which is dominant in early acute psoriasis, is relayed by TNF–IL-23–Th17-driven inflammation mediated by T cells in chronic plaque psoriasis. Interestingly, IL-17 and IL-22 induce the expression of antimicrobial peptides in keratinocytes, leading to a self-sustained feedback loop and chronification of the disease. Moreover, pDCs have been identified as a mediator of cytokine IL-36 activity and are implicated in the IL-36/TLR9 pathway, which upregulates systemic type I IFN activation in psoriasis.[48]

Mehta et al.[49] analysed mononuclear phagocytes and T cells of skin from patients before and during treatment with guselkumab or secukinumab using high-dimensional unsupervised flow cytometry. Among the assessed phagocytes they found that CD64brightCD163CD14brightCD1cCD1a inflammatory monocyte-like cells were the predominant source of IL-23 and that these cells, together with CD64CD163CD14IL-23p19TNF-α+ inflammatory dendritic-like cells, were increased in lesional vs. non-lesional skin from the same patient. With regard to drug effects, they reported that neither drug modified the frequencies of IL-17A+IL-17F+/CD4+ or CD8+ T cells but found that the IL-23 antagonist guselkumab reduced memory T cells while maintaining regulatory T cells (Tregs), whereas the opposite effect was observed with the IL-17 antagonist secukinumab.

The Koebner phenomenon refers to the occurrence of psoriatic lesions in a previously unaffected area following another type of skin injury to the area. Epidermal trauma induces expression of antimicrobial peptides in the skin and drives the pathogenic immune response as described above. In addition, induction of scratch injury on keratinocytes showed upregulated mRNA expression and protein secretion of CCL20 and CXCL8, suggesting another potential mechanism for its induction.[50] Another hypothesis is mechanical stretch-induced adenosine triphosphate release from keratinocytes, which can trigger the Koebner phenomenon in psoriasis.[51] A number of inflammatory mediators, including IL-6, IL-8, IL-17 and IL-36γ, as well as changes in the ratio of CD4+/CD8+ T cells, have also previously been reported to play a role in the induction of the Koebner phenomenon.[52]

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