Psoriasis is a common disease, characterised by thick erythematous skin plaques and scaling, as
well as a range of associated conditions, including psoriatic arthritis. Psoriatic skin lesions are
characterised by excessive inflammation, leukocyte infiltration and production of chemokines,
the primary regulators of leukocyte migration. The chemokines that drive immune cell recruitment
to the lesions, sequence of migratory events, and drug effects on leukocyte migration remain
poorly understood. Therefore, we have investigated the chemokine-orchestrated leukocyte
migration events in psoriasis and how they might be affected by current in-use drugs for the
treatment of psoriasis. Using a transwell system, which assays cell chemotaxis towards a specific
chemoattractant, we demonstrate that CXCL8 and CCL20 are important drivers of lesion
recruitment of neutrophils and T-cells respectively in psoriasis. Furthermore, neutrophils and Tcells derived from patients with psoriasis had an increased responsiveness to CXCL8 and CCL20,
respectively. Additioally, we also demonstrate that the increase in CXCL8 responsiveness is
diminished in patients treated with the PDE4 inhibitor Apremilast. Strikingly, Apremilast
treatment of neutrophils led to the abolishment of intracellular calcium fluxes, known to be
related to reduced neutrophil migration. Further to this, we show that Apremilast treatment of
mice with psoriasiform inflammation significantly reduced neutrophil influx into the lesions.
Interactions of leukocytes with keratinocytes have been previously linked to the elevated
production of multiple pro-inflammatory mediators. Here we report that CCL20-responsive Tcells, derived from patients with psoriasis, were able to induce the production of neutrophil
attracting factors by keratinocytes. On the contrary, CXCL8-responsive neutrophils, derived
from patients with psoriasis, were not able to induce the production of T-cell attracting factors
by keratinocytes. The data suggest that immune-stromal cell interactions can influence immune
cell recruitment in psoriasis, but more work is required to determine whether or not this is a
fundamental pathway that can be targeted.
