The Relapse of Psoriasis: Mechanisms and Mysteries

Abstract

Over the past decades, tremendous success in the treatment of psoriasis has been achieved using biologics, such as neutralizing antibodies against TNF/TNFR, IL-23, and IL-17A/IL-17RA. Although psoriatic skin lesions appear to resolve after treatment with these biologics, lesions often recur after therapy is discontinued or during therapy. Memory T cells residing in the skin have been considered as the major driver of psoriasis relapse. However, whether structural cells in the skin such as keratinocytes and fibroblasts are involved in the relapse of psoriasis is unknown. In this review, we outline the therapeutic rationale of biologics used in the treatment of psoriasis, summarize different clinical features of psoriasis relapse on the basis of preclinical and clinical data, and specifically discuss how memory T cells and structural cells in the skin are involved in psoriasis relapse. Finally, we discuss the future challenges in the basic or clinical research on psoriasis.

Keywords: AMP, antimicrobial peptides/proteins; EpSC, epithelial stem cell; FDA, Food and Drug Administration; H3K27, histone 3 lysine 27; H3K27ac, histone 3 lysine 27 acetylation; H3K4me3, histone 3 lysine 4 trimethylation; ILC3, innate lymphoid cell 3; IMQ, imiquimod; KC, keratinocyte; PGA, Physician Global Assessment; STAT3, signal transducer and activator of transcription 3; TLR, toll-like receptor; TRM, resident memory T cell; Th, T helper; Treg, regulatory T cell; hBD, human beta-defensin; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell.

Figure 1

A feed-forward inflammatory loop in psoriasis. When trauma occurs, nucleic acids, AMPs, and other factors are released from stressed cells or damaged cells. Among these, AMPs complex with DNA or RNA to form multimeric AMP‒nucleic acid complexes, which activate TLR7/8 to induce the production of type I IFNs in pDCs or increase amounts of IL-6 and TNF-α by mDCs. IL-6, together with TGFβ, induces CD4⁺ naive T-cell differentiation into Th17 cells, and TNF-α and IL-1β further enhance Th17 differentiation, whereas type I IFNs and TNF-α activate mDCs to produce IL-12 and IL-23. IL-12 induces CD4⁺ naive T-cell differentiation into Th1 cells that can produce IFN-γ, and IL-23 promotes Th17 cells, γδT cells, and ILC3 to produce high levels of IL-17A, IL-22, and TNF-α. All these cytokines act on keratinocytes to induce epidermal hyperproliferation or induce keratinocytes to constantly produce proinflammatory cytokines, chemokines, and AMPs. Again, AMPs complex with nucleic acids to activate pDCs or mDCs to express more IL-6, TNF-α, IL-12, IL-23, and type I IFNs for the expansion of IL-17‒producing cells. Chemokines such as CCL20 and CXCL1 recruit more neutrophils or IL-17‒producing cells to the site of inflammation in the skin. All these comprise a feed-forward loop to further amplify local inflammatory responses and epidermal hyperplasia. AMP, antimicrobial protein; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; Th, T helper; TLR, toll-like receptor.

Figure 2

CD8⁺ T_RM cells and keratinocytes with inflammatory memory in psoriasis relapse. In skin lesions, IL-17‒producing cells, CD8⁺T_RM, and Vγ4⁺Vδ4⁺T cells are activated to produce multiple cytokines, including IL-23, IL-17A, and IL-22, which activate STAT3 and general stress-responsive transcription factors FOS and JUN in EpSCs (also named basal keratinocytes). Moreover, several inflammatory cytokines promote H3K27ac at distal enhancers or H3K4me3 at the promoters of stimulated genes, thus increasing the chromatin accessibility in EpSCs. FOS partners with JUN, and then STAT3 directs FOS‒JUN to MDs, the chromatin regions that gain accessibility during the inflammatory response and remain so after resolution, for establishing inflammatory memory in EpSCs. After resolution of inflammation, CD8⁺T_RM and Vγ4⁺Vδ4⁺T cells retain in resolved skin, and STAT3 and FOS are released from the MDs, but H3K4me1, monomethylated H3K4 derived from H3K4me3, and JUN with other homeostatic transcriptional factors such as ATF3 and p63 remain on MDs to maintain chromatin opening in EpSCs. On secondary challenges such as wounding and infections, FOS is rapidly rerecruited to MDs and couples with JUN to reactivate gene expression in EpSCs, and CD8⁺T_RM and Vγ4⁺Vδ4⁺T cells produce IL-17A, thus reinitiating inflammatory loops in the skin and triggering psoriasis relapse. The bottom panel is adapted from Larsen et al. (2021). EpSC, epithelial stem cell; H3K27ac, histone 3 lysine 27 acetylation; H3K4, histone 3 lysine 4; H3K4me3, histone 3 lysine 4 trimethylation; MD, memory domain; STAT3, signal transducer and activator of transcription 3; T_RM, resident memory T cell.