Abstract
Accumulating evidence on the role of Thrombospondin-1 (TSP-1) in the immune response has emerged during the last years. In spite of the importance of TSP-1 not only as anti-angiogenic factor but also as an immunomodulatory molecule, studies on the role of TSP-1 in psoriasis have been neglected. TSP-1 and CD47 expression were analyzed in skin samples from psoriasis patients and control subjects using RT-PCR and immunofluorescence. Expression of these molecules was also evaluated in peripheral blood CD4+ T cells, moDCs, and circulating primary DCs. The functional role of TSP-1/CD47 signaling axis in psoriasis was assessed in Th17 and Treg differentiation assays. Additionally, small interfering RNA assays specific to TSP-1 were performed in CD4+ T cells and monocyte derived DC to specifically evaluate the function of this protein. Lesional skin of psoriasis patients expressed lower TSP-1 and CD47 mRNA levels compared to non-lesional skin or skin from controls. Immunofluorescence staining revealed decreased expression of CD47 in CD45+ dermal cells from psoriasis samples compared to control subjects. Peripheral CD4+ T cells and circulating primary DCs from psoriasis also expressed lower levels of CD47 compared to controls. Although no significant differences were detected in TSP-1 expression in CD4+ T cells and moDCs between patients and controls, TSP-1 expression in psoriasis patients inversely correlated with disease activity evaluated by the Psoriasis Area and Index Activity. Furthermore, exogenous TSP-1 inhibited Th17 differentiation and stimulated the differentiation of CD4+ T cells toward Treg cells. Furthermore, RNA interference specific for TSP-1 confirmed the role of this molecule as a negative regulator of T cell activation. Because of the impact of TSP-1/CD47 signaling axis in Th17 and Treg differentiation, a dysregulated expression of these molecules in the immune cells from psoriasis patients may favor the exacerbated inflammatory response in this disease.
Highlights
Psoriasis is considered a chronic inflammatory autoimmune disease characterized by exacerbated proliferation and disturbed keratinocyte maturation, inflammatory dermal infiltrates and changes of the superficial microvasculature that result in an angiogenic phenotype [1]
Our data showed that lesional skin from psoriasis patients express lower levels of TSP-1 and CD47 compared to nonlesional skin or skin from control subjects (Figures 1A,B)
In this study we identified a defective expression of CD47 locally in dermal leukocytes, and in CD4+ T lymphocytes, plasmacytoid DCs (pDCs), and myeloid DCs (mDCs) from peripheral blood
Summary
Psoriasis is considered a chronic inflammatory autoimmune disease characterized by exacerbated proliferation and disturbed keratinocyte maturation, inflammatory dermal infiltrates and changes of the superficial microvasculature that result in an angiogenic phenotype [1]. Clinical investigations and experimental studies indicate that IFN-γ-producing T helper type (Th) cells and CD4+ Th17 cells accompanied by increased expression of IL-17A and accumulation of CD8+ cytotoxic T cells in psoriatic lesions cooperate at the interface of innate and adaptive immunity by activating keratinocytes to produce IL-17C This cytokine together with other keratinocyte-derived mediators sustains chronic inflammation in psoriatic plaques [3,4,5]. TSP-1 regulates multiple cellular events involved in tissue repair including cell adhesion, migration, proliferation, extracellular matrix expression and organization, and regulation of growth factor activity [8] This is possible due to its multi-domain structure which interacts with several cell receptors and matrix proteins [9]. Despite TSP-1 is mostly known for its role in modifying the tumor micro-environment through its anti-angiogenic properties [10], growing evidence about the role of TSP-1 in immune response has emerged in the last decade [11,12,13]
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