Depletion of antigen-presenting cells by clodronate liposomes reverses the psoriatic skin phenotype in KC-Tie2 mice

作者：Ward N L^*; Loyd C M; Wolfram J A; Diaconu D; Michaels C M; McCormick T S

来源：British Journal of Dermatology, 2011, 164(4): 750-758.

DOI：10.1111/j.1365-2133.2010.10129.x

P>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)-1 alpha, IL-6, IL-23 and tumour necrosis factor (TNF)-alpha expression and modest reductions in interferon-gamma and IL-17.
Conclusions
These findings suggest a critical role for APCs and myeloid cell-derived IL-23 and TNF-alpha and underscore the importance of Th1 and Th17 T cells in maintaining the psoriasiform skin phenotype in the KC-Tie2 mouse model.

• 出版日期2011-4-11