Scanning the Immunopathogenesis of Psoriasis

Abstract

Psoriasis is a chronic inflammatory skin disease, the immunologic model of which has been profoundly revised following recent advances in the understanding of its pathophysiology. In the current model, a crosstalk between keratinocytes, neutrophils, mast cells, T cells, and dendritic cells is thought to create inflammatory and pro-proliferative circuits mediated by chemokines and cytokines. Various triggers, including recently identified autoantigens, Toll-like receptor agonists, chemerin, and thymic stromal lymphopoietin may activate the pathogenic cascade resulting in enhanced production of pro-inflammatory and proliferation-inducing mediators such as interleukin (IL)-17, tumor necrosis factor (TNF)-α, IL-23, IL-22, interferon (IFN)-α, and IFN-γ by immune cells. Among these key cytokines lie therapeutic targets for currently approved antipsoriatic therapies. This review aims to provide a comprehensive overview on the immune-mediated mechanisms characterizing the current pathogenic model of psoriasis.

Keywords: IL-17; IL-23; autoantigen; autoreactive T cells; chemokines; cytokines; dendritic cells; immunology; pathogenesis; psoriasis.

Figure 1

The pathogenic model based on the IL-23/IL-17 axis inducing the development of psoriatic phenotype. Multiple factors induce mDCs activation with consequent IL-23 production (IFN-α, TSLP), that, in turn, stimulates mainly T cell subsets, but also ILC3, mast cells, and neutrophils, to secrete IL-17. Other cytokines derived from T cells, mast cells, and ILC3 (IL-22, IL-17F, and IL-21), and from mDCs (TNFα, NO, and IL-20) contribute to the development of psoriatic skin. Autoantigens involved in this pathway are highlighted in yellow. T17 and T22 cells represent all T cell subsets producing mainly IL-17 and IL-22, respectively. The IL-23/IL17 axis, the main immune pathway in psoriasis pathogenesis, is highlighted in red, while the other immune signals are designed in blue. CCL: CC chemokine ligands; CXCL: chemokine (C-X-C motif) ligand; ADAMTSL5: Thrombospondin Type 1 motif-like 5; β-DEF: β-defenins; IFN: interferon; IL: interleukin; KC: keratinocyte; mDC: myeloid Dendritic Cell; NKT: Natural Killer T cell; NO: nitric oxide; pDC: plasmacytoid Dendritic Cells; TNF: tumor necrosis factor; TSLP: Thymic stromal lymphopoietin.

Figure 2

Therapeutic “hierarchy” of pathogenic cytokines in psoriasis. (A) The shooting target shows the best targets for treatment of psoriasis (IL-17, IL-23, and TNF-α). Moving away from the center, other pathogenic cytokines have proved to be less therapeutically relevant because their blockade resulted in a poor clinical response [11,128,129,130,131,132]; (B) key-cytokines (IFNα, TNFα, IL-23, and IL-17) in upstream and downstream points within the psoriatic inflammatory cascade, and other relevant contributors: IFN-γ, IL-22, IL-1F9, IL-8, and CCL20. CCL: CC chemokine ligands; IFN: interferon; IL: interleukin; TNF: tumor necrosis factor.

Figure 3

Feed-forward inflammatory circuits involving keratinocytes. IL-17 auto-amplifies its signal through the stimulation of keratinocytes which then produce CCL20 (A) or other chemoattractans (B) recruiting IL-17-producing T cells (A) and other inflammatory cells. In a similar auto-sustaining manner, IFN-γ-secreting T cells are recruited through keratinocyte production of chemokines (CXCL9-11) induced by IFN-γ (C). CCL: CC chemokine ligands; CCR: C-C chemokine receptor; CXCL: chemokine (C-X-C motif) ligand; CXCR: C-X-C motif chemokine receptor; IFN: interferon; IL: interleukin; KC: keratinocyte; Th: T helper; Tc: T cytotoxic; TNF: tumor necrosis factor.

Figure 4

Activation of pDCs. Self-nucleic acids (both DNA and RNA) derived from damaged cells when complexed with AMPs, including LL37, and Th17-derived cytokine IL-26, can activate pDCs through TLR activation. pDCs migration and activation can be also induced by chemerin, an inflammatory protein mainly secreted by fibroblasts. pDCs: plasmacytoid Dendritic Cells; TLR: Toll-like Receptor.