Depletion of antigen-presenting cells by clodronate liposomes reverses the psoriatic skin phenotype in KC-Tie2 mice
- 11 November 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in British Journal of Dermatology
- Vol. 164 (4), 750-758
- https://doi.org/10.1111/j.1365-2133.2010.10129.x
Abstract
Background There is ongoing debate regarding the initiation of psoriatic plaque as primarily arising from an anomaly in epidermal keratinocytes (KCs) or from abnormalities in immunocytes that secondarily activate otherwise normal KCs. In mice engineered to overexpress the angiopoietin receptor Tie2 in KCs, skin spontaneously develops the characteristic clinical, histological and immune cell phenotypes of psoriasis which can be reversed with either transgene repression or ciclosporin administration, suggesting key roles for both KCs and T cells in mediating the skin disease in this murine model. Objectives To determine if antigen‐presenting cells (APCs) and macrophages alone are sufficient to sustain psoriasiform inflammation in the KC‐Tie2 murine model of psoriasis. Methods Clodronate liposomes were intradermally injected into involved dorsal skin of KC‐Tie2 or control animals once a week for 6 weeks and acanthosis, angiogenesis, immune cell infiltration and cytokine production were quantitated using immunohistochemistry and interactive image analyses, enzyme‐linked immunosorbent assay (ELISAs) and quantitative real‐time polymerase chain reaction (qRT‐PCR). Results Clodronate liposome injection eliminated CD11c+, F4/80+ and CD11b+ cells in the skin and returned CD8+ T‐cell numbers to control mouse levels. APC depletion in KC‐Tie2 mouse skin resulted in resolution of the acanthotic skin phenotype, decreased dermal angiogenesis, and a return to control mouse levels for interleukin (IL)‐1α, IL‐6, IL‐23 and tumour necrosis factor (TNF)‐α expression and modest reductions in interferon‐γ and IL‐17. Conclusions These findings suggest a critical role for APCs and myeloid cell‐derived IL‐23 and TNF‐α and underscore the importance of Th1 and Th17 T cells in maintaining the psoriasiform skin phenotype in the KC‐Tie2 mouse model.Keywords
This publication has 44 references indexed in Scilit:
- Keratinocyte but Not Endothelial Cell-Specific Overexpression of Tie2 Leads to the Development of PsoriasisThe American Journal of Pathology, 2009
- Effect of depletion of monocytes/macrophages on early aortic valve lesion in experimental hyperlipidemiaCell and tissue research, 2009
- T-Helper 17 Cells in Psoriatic Plaques and Additional Genetic Links between IL-23 and PsoriasisJournal of Investigative Dermatology, 2008
- Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2)The Lancet, 2008
- Activated macrophages are essential in a murine model for T cell-mediated chronic psoriasiform skin inflammationJCI Insight, 2006
- Pathogenic role for skin macrophages in a mouse model of keratinocyte-induced psoriasis-like skin inflammationJCI Insight, 2006
- Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteinsNature, 2005
- Infliximab induction therapy for patients with severe plaque-type psoriasis: A randomized, double-blind, placebo-controlled trialJournal of the American Academy of Dermatology, 2004
- Etanercept treatment of psoriatic arthritis: Safety, efficacy, and effect on disease progressionArthritis & Rheumatism, 2004
- A 50% reduction in the Psoriasis Area and Severity Index (PASI 50) is a clinically significant endpoint in the assessment of psoriasisJournal of the American Academy of Dermatology, 2004