Keratinocyte Apoptosis in Epidermal Remodeling and Clearance of Psoriasis Induced by UV Radiation

Psoriasis is a common chronic skin disorder, but the mechanisms involved in the resolution and clearance of plaques remain poorly defined. We investigated the mechanism of action of UVB, which is highly effective in clearing psoriasis and inducing remission, and tested the hypothesis that apoptosis is a key mechanism. To distinguish bystander effects, equal erythemal doses of two UVB wavelengths were compared following in vivo irradiation of psoriatic plaques; one is clinically effective (311 nm) and one has no therapeutic effect on psoriasis (290 nm). Only 311 nm UVB induced significant apoptosis in lesional epidermis, and most apoptotic cells were keratinocytes. To determine clinical relevance, we created a computational model of psoriatic epidermis. Modeling predicted apoptosis would occur in both stem and transit-amplifying cells to account for plaque clearance; this was confirmed and quantified experimentally. The median rate of keratinocyte apoptosis from onset to cell death was 20 minutes. These data were fed back into the model and demonstrated that the observed level of keratinocyte apoptosis was sufficient to explain UVB-induced plaque resolution. Our human studies combined with a systems biology approach demonstrate that keratinocyte apoptosis is a key mechanism in psoriatic plaques clearance, providing the basis for future molecular investigation and therapeutic development

Management of psoriasis in pregnancy

Many treatments for this chronic skin disease are harmful to the developing fetus, so careful pre-conception planning and management adjustment are crucial for the pregnant patien

Supplementary material.

A. Model details. B. Bimodal behaviour of the model. C. Parameter sensitivity analysis. D. Growth and differentiation rate of keratinocytes. E. Keratinocytes growth vs. epidermis cell density. F. Apoptosis and Desquamation Rates. G. Supplementary figures. Fig A. Phase planes demonstrating the effect of changing initial values of DC and TA species on converging to the two stable steady states of the model. Fig B. Parameter sensitivity analysis. Fig C. Model simulations of 1x weekly UVB phototherapy (30 doses) vs. UVB sensitivity. Fig D. Model simulation of UVB-induced cell apoptosis vs. cell growth arrest. Fig E. Modelling flares by introducing an immune stimulus to the model. (PDF)</p

PASI measurements and UVB doses over the first three weeks of the therapy are sufficient to predict the UVB sensitivity <i>uvb</i>_<i>s</i> parameter, which allows high-accuracy model personalisation.

Panels: (a,b)—results of parameter fitting for two different patients; (c)—distribution (n = 754) of the difference between the model PASI simulation Ψ* and the patients’ actual PASI data; (d)—distribution (n = 754) of the absolute value of the difference between the model simulation and patients’ PASI data; (e)—distribution (n = 738) of relative PASI difference calculated as a ratio between the absolute PASI difference and the corresponding PASI value (excluding those values for which corresponding PASI = 0; n = 16), (f)—results of fitting uvbs after 3 weeks with respect to fitting uvbs at the end of the therapy.</p

ODE psoriasis model demonstrates that UVB-induced apoptosis leads to psoriasis clearance.

Simulation of the model response to a 10-week course of UVB phototherapy. Panels: (a)—simulated UVB irradiation regime, (b)—cell densities, where SC—stem cells, TA—transit-amplifying cells, D—differentiating cells, DC—dendritic cells, T—T cells, Σ = SC + TA + D + DC + T—total cell density, T and DC dynamics overlap and are represented by alternating colours, (c)—cytokines concentration, where IL17/22—interleukin-17/22, IL23—interleukin-23, TNF—tumour necrosis factor alpha, GF—keratinocyte-derived growth factors, TNF and IL17/22 dynamics overlap and are represented by alternating colours, (d)—number of apoptotic cells per 1,000 cells.</p

Steady states of the model.

Steady states of the model.</p

Our ODE model of epidermis describes an explicit interaction between the main types of keratinocytes and immune cells mediating psoriasis.

Panels: (a)—mechanism of interaction between the main cell types and cytokines in epidermis; (b)—interactions between the species of our model, where SC—stem cells, TA—transit-amplifying cells, D—differentiating cells, DC—dendritic cells, T—T cells, A—apoptotic cells, IL17/22—interleukin-17/22, IL23—interleukin-23, TNFα—tumour necrosis factor alpha, GF—keratinocyte-derived growth factors, and ⌀—degradation species; (c)—cell density (cells/mm2) for every cell type (excluding apoptotic cells) in the healthy (non-lesional skin), psoriatic (lesional/plaque skin) and transition steady states.</p

The speed of psoriasis onset in ODE model depends on the strength and the duration of the immune stimulus.

Panels: (a)—heatmap where white-coloured area denotes combinations of immune stimulus strength and duration that do not lead to psoriasis; other colours denote psoriasis; (b) and (c)—examples of model simulations for the combinations of stimulus strength and duration values, as highlighted in Panel (a), leading to fast and slow psoriasis onsets, respectively. Psoriasis onset occurs if totC = totCH + 0.9(totCP − totCH) ≈ 247,376 cells/mm2 ≈ 0.93 ⋅ totCP (i.e., the total cell density of the model has covered 90% of the distance between the healthy state and the psoriatic state—see Table 2 for the actual cell densities). This is due to the relatively slow convergence of the model to the psoriatic steady state.</p