Inhibition of CCR7/CCL19 axis in psoriatic plaques is an early critical event for the clinical response to anti-TNF Therapy in psoriasis patients

Introduction Psoriasis is a chronic inflammatory skin disease affecting approximately 2% of the population. Important clinical benefits in the treatment of psoriasis have been obtained with TNF inhibitors, which have also contributed to the understanding of mechanisms involved in the disease pathogenesis. Despite the evidence that TNF-inhibitors block the inflammatory cascade and induce a decrease of Th17 responses in the psoriatic plaques, their primary mechanism of action in inhibiting the self-sustaining pathogenic cycle in psoriasis is not completely understood [1], [2] and [3]. In this study we want to identify the early key events for the resolution of inflammation in psoriatic skin lesions upon treatment with TNF inhibitors. Methods We used a translational approach combining quantitative gene expression analysis, clinical parameter of disease severity (PASI) and immunofluorescence analysis on tissue sections. Punch biopsies were collected from lesional skin at baseline and after 4 weeks of anti-TNF therapy (Etanercept, Infliximab or Adalimumab) and gene expression levels were evaluated by qRT-PCR performed by TaqMan Low Density Array (Human Immune Panel). The correlation between changes of gene expression in lesional skin and the decrease of PASI score after treatment was calculated with Spearman’s rank correlation test. Data were validated by immunofluorescence microscopy on skin biopsies collected at baseline and after anti-TNF therapy (4 weeks). Results We found that among genes down-modulated by TNF inhibitors, the ones that mostly associated with clinical remission were Ccr7, its ligand Ccl19 and dendritic cell maturation genes. Clinical remission was also associated with the decreased expression of T cell activation genes and Vegf. Importantly, the down-regulation of Ccr7 observed at 4 weeks also correlated with the clinical remission occurring at later time points. Immunofluorescence microscopy on skin biopsies showed that reduction of CCR7+ cells and CCL19 was paralleled by disaggregation of the dermal lymphoid-like tissue in the psoriatic plaque. Conclusion These data show that early critical events for psoriasis resolution induced by TNF-blockade are the inhibition of CCR7/CCL19 axis and the disaggregation of the lymphoid-like tissue in the upper derma. This strongly supports the role of dermal lymphoid aggregate formation mediated by CCR7/CCL19 interaction in the pathogenesis of psoriasis.