Skin Patterning in Psoriasis by Spatial Interactions between Pathogenic Cytokines

Abstract

Disorders of human skin manifest themselves with patterns of lesions ranging from simple scattered spots to complex rings and spirals. These patterns are an essential characteristic of skin disease, yet the mechanisms through which they arise remain unknown. Here we show that all known patterns of psoriasis, a common inflammatory skin disease, can be explained in terms of reaction-diffusion. We constructed a computational model based on the known interactions between the main pathogenic cytokines: interleukins IL-17 and IL-23, and tumor necrosis factor TNF-α. Simulations revealed that the parameter space of the model contained all classes of psoriatic lesion patterns. They also faithfully reproduced the growth and evolution of the plaques and the response to treatment by cytokine targeting. Thus the pathogenesis of inflammatory diseases, such as psoriasis, may be readily understood in the framework of the stimulatory and inhibitory interactions between a few diffusing mediators.

Keywords: Biological Sciences; Dermatology; in silico biology.

Graphical abstract

Figure 1

Patterns of Skin Lesions in Psoriasis See also Figure S1.

Figure 2

Modeling Plaque Formation in Psoriasis (A) Interactions between key cytokines involved in psoriasis plaque formation. Labels numbered 0–4 refer to the observations from which these interactions have been inferred (see Results). (B) A simplified diagram of interactions, in which cytokines IL-17 and TNF-α are considered jointly. (C) Diagram (B) relabeled as an activator (A) - depleted substrate (S) system. (D) Skin representation and simulation initialization. The skin surface is partitioned into square regions. A lesion is initiated by an activated T_H17 cell (red), which is either a resident memory T cell activated by a dendritic cell (green, interaction a) or has migrated from circulation through a capillary wall (interaction b). The area of microinflammation around the activated T_H17 cell is considered as a “seed” region, and its projection to the surface (arrow c) is colored in red. The epidermis, the upper layer of the skin, is shaded in gray and capillaries in the dermis are colored in red (arterioles) and blue (venules). Skin-resident memory T cells are marked in gray. (E) Detail of skin surface representation. Each region is a two-dimensional projection of the underlying activator-depleted substrate system of proinflammatory cytokines and represents a computational cell implementing reaction system (C). These computational cells are interconnected (double arrows), allowing for the diffusion of cytokines.

Figure 3

Parameter Space of the Model and Selected Patterns Top left: A comprehensive representation of the range of patterns generated using Equation 2 for different values of the synthetic parameters c and f. (A–D) Magnified views of patterns generated using select parameter values. These labels and patterns correspond to the psoriatic skin lesions identified in Figure 1.

Figure 4

The Simulated Progression of Different Types of Psoriatic Lesions Rows 1–3: Development of the lesions. The earliest stage of a papule (Row 1) consists of randomly distributed small seed areas. Later forms of the disease (Rows 2 and 3) correspond to patterns identified in Figures 1 and 3. Rows 4–6: The effect of treatment simulated by increasing the decay rate of IL-17 and TNF-α. Note that the treatment does not result in a simple reversal of the original pattern development, but produces residual lesions with more activity at the margin of the plaques (Row 5). In some instances, residual papules persist (Row 6).