Chemokine orchestration of leukocyte-skin interactions

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.