Systemic anti-VEGF treatment strongly reduces skin inflammation in a mouse model of psoriasis

Abstract

Although , vascular remodeling is a hallmark of many chronic inflammatory disorders such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, anti-vascular strategies to treat these conditions have received little attention to date. We investigated the anti-inflammatory activity of systemic blockade of VEGF-A by the inhibitory monoclonal antibody G6 -31, employing a therapeutic trial in a mouse model of psoriasis. Simultaneous deletion of JunB and c-Jun (DKO*) in the epidermis of adult mice leads to a psoriasis-like phenotype with hyper-and parakeratosis and increased subepidermal vascularization. Moreover, an inflammatory infiltrate and elevated levels of cytokines/chemokines including TNF␣, IL-1␣/␤, IL-6, and the innate immune mediators IL-22, IL-23, IL-23R, and IL-12p40 are detected. Here we show that anti-VEGF antibody treatment of mice already displaying disease symptoms resulted in an overall improvement of the psoriatic lesions leading to a reduction in the number of blood vessels and a significant decrease in the size of dermal blood and lymphatic vessels. Importantly, anti-VEGF-treated mice showed a pronounced reduction of inflammatory cells within the dermis and a normalization of epidermal differentiation. These results demonstrate that systemic blockade of VEGF by an inhibitory antibody might be used to treat patients who have inflammatory skin disorders such as psoriasis.activator protein-1 ͉ Jun proteins ͉ epidermis ͉ angiogenesis ͉ G6-31 antibody

Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation

“…Specific inhibition of VEGF-A also ameliorated psoriasis-like symptoms in a mouse model of psoriasis, where the epidermal specific deletion of c-Jun and JunB leads to the disease (Schonthaler et al, 2009). Together, these results indicate an important role of angiogenesis and blood vascular activation in sustaining chronic inflammation.…”

“…Images of three to four individual fields of view were acquired per section using AxioVision software 4.7.1 (Carl Zeiss, Inc.). Computer-assisted analyses of digital images were performed using the IP-LABORATORY software (Scanalytics) as previously described (Schonthaler et al, 2009). The mean lymphatic and blood vessel number per millimeter of epidermal basement membrane and the mean size of CD31 + /LYVE-1 + lymphatic and of CD31 + /LYVE-1  or MECA-32 + blood vessels were determined in the area of one ear half between cartilage and stratum corneum.…”

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

“…Hyperplastic lymphatics in chronic diseases such as psoriasis, inflammatory bowel disease, chronically-inflamed skin disease and rheumatoid arthritis have negative implications for disease resolution. For these conditions, treatment with anti-VEGF antibodies can, in some cases, promote disease resolution [106][107][108][109]. Furthermore, while vascular angiogenesis can be reversed in chronic inflammation, lymphangiogenic structures seem to persist [103,110].…”

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

“…After therapy, a reduction in vessel density and diameter was observed, corresponding to a reduction in severity of skin lesions (Schonthaler et al 2009). Clinical case reports have also suggested improvement in skin lesions after treatment with anti-VEGFR TKIs (Keshtgarpour and Dudek 2007;Fournier and Tisman 2010;Narayanan et al 2010).…”