title: Inhibition of CCR7/CCL19 axis in lesional skin is a critical event for clinical remission induced by TNF blockade in patients with psoriasis.
abstract: Despite the evidence that tumor necrosis factor (TNF) inhibitors block TNF and the downstream inflammatory cascade, their primary mechanism of action in inhibiting the self-sustaining pathogenic cycle in psoriasis is not completely understood. This study has the aim to identify early critical events for the resolution of inflammation in skin lesions using anti-TNF therapy. We used a translational approach that correlates gene expression fold change in lesional skin with the Psoriasis Area and Severity Index score decrease induced by TNF blockade after 4 weeks of treatment. Data were validated by immunofluorescence microscopy on skin biopsy specimens. We found that the anti-TNF-modulated genes that mostly associated with the clinical amelioration were Ccr7, its ligand, Ccl19, and dendritic cell maturation genes. Decreased expression of T-cell activation genes and Vegf also associated with the clinical response. More important, the down-regulation of Ccr7 observed at 4 weeks significantly correlated with the clinical remission occurring at later time points. Immunofluorescence microscopy on skin biopsy specimens showed that reduction of CCR7(+) cells and chemokine ligand (CCL) 19 was paralleled by disaggregation of the dermal lymphoid-like tissue. These data show that an early critical event for the clinical remission of psoriasis in response to TNF inhibitors is the inhibition of the CCR7/CCL19 axis and support its role in psoriasis pathogenesis.
authors.affiliation: Laboratory of Translational Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Ortopedico Galeazzi, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bosè
authors.forename: Luciana
authors.initials: L
authors.lastname: Petti
authors.forename: Marco
authors.initials: M
authors.lastname: Diani
authors.forename: Claudia
authors.initials: C
authors.lastname: Moscheni
authors.forename: Silvia
authors.initials: S
authors.lastname: Molteni
authors.forename: Andrea
authors.initials: A
authors.lastname: Altomare
authors.forename: Riccardo L
authors.initials: RL
authors.lastname: Rossi
authors.forename: Daniela
authors.initials: D
authors.lastname: Talarico
authors.forename: Raffaella
authors.initials: R
authors.lastname: Fontana
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Russo
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Altomare
authors.forename: Eva
authors.initials: E
authors.lastname: Reali
mesh_terms: D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D015704:CD4 Antigens / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects; D054415:Chemokine CCL19 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D000069285:Infliximab; D007801:Langerhans Cells / Q000187:drug effects; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000188:drug therapy* / Q000235:genetics; D054400:Receptors, CCR7 / Q000037:antagonists & inhibitors* / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D012074:Remission Induction; D012867:Skin / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C515370:CCR7 protein, human; D015704:CD4 Antigens; D054415:Chemokine CCL19; D007074:Immunoglobulin G; D054400:Receptors, CCR7; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept