Role And Mechanism Of Progranulin In Psoriasis Vulgaris

Objective:Psoriasis vulgaris is a common and chronic recurrent inflammatory skin disease characterized by red, scaly, raised plaques. Psoriasis vulgaris has defining histopathological features, including epidermal hyperplasia, increased dermal angiogenesis, and dense infiltrates of immunocytes. Although the pathogenesis of psoriasis has not been fully elucidated, tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) are overexpressed in psoriasis and are believed to have central roles in the processes.Progranulin (PGRN) is an autocrine growth factor with multiple physiological and pathological functions, which is widely expressed in various tissues especially in rapidly growing cells. PGRN is known to play a critical role in variety of physiologic and disease processes, including early embryogenesis, wound healing, tumorigenesis, and neuroproliferative and degenerative disease. Recently, PGRN was discovered as a multifaceted immune-regulatory molecule, which has dual roles in inflammation and exerts anti-inflammation and proinflammatory function in different diseases through regulating the different signaling pathways known to be critical for immunology. PGRN has been found to be a novel ligand of TNF receptors (TNFR). PGRN blocks TNF-a-mediated signaling pathways by competing with TNF-a binding to TNFR1/2 and exhibits anti-inflammatory function in inflammatory arthritis models. In contrast to its anti-inflammatory role, PGRN also has pro-inflammatory effects in obesity and insulin-resistant diabetes through production of IL-6. However, the expression and role of PGRN in psoriasis has not been fully investigated. In this study, we will detecte the expression of PGRN in patients with psoriasis vulgaris and mouse model of psoriasis; evaluate the impact on mouse model of psoriasis by deleting pgrn gene; and then explore the role and mechanism of PGRN in psoriasis vulgaris.Method:A total of 34 patients with psoriasis vulgaris together with 20 age-and sex-matched controls, were included into the study. The diagnosis of psoriasis vulgaris was made on the basis of typical clinical manifestation and histopathology. The severity of disease in patients was evaluated using Psoriasis Area and Severity Index (PASI) before and after treatment. The peripheral blood and skin lesions of patients were collected. The mRNA and protein expression of PGRN in skin specimens were examined by qRT-PCR and immunohistochemical staining. ELISA analysis was used to detecte the serum levels of PGRN, TNF-a and IL-6 in patients with psoriasis vulgaris and normal individuals.10-12 weeks old male wild-type (WT) mice were purchased, and the ears of mice were treated with 0.01% TPA to induce psoriasis-like inflammation. Immunohistochemical staining and qRT-PCR were applied to assess the protein and mRNA expression of PGRN in the ears of untreated and TPA-treated WT mice.The C57BL/6 background PGRN-/- mice were purchased and 10-12 weeks old male PGRN-/- mice along with their WT counterparts were used for these experiments. After 0.01% TPA treatment, we analyzed the difference of psoriasis-like inflammation in two groups of mice both from lesional appearance and histological characteristics. And then we studied the CD4+ T cell subsets in the ears and cervical lymph nodes by flow cytometry to determine the cellular basis for the differences in the inflammatory response between PGRN-/- mice and WT mice.Results:In this study, we found that both mRNA and protein levels of PGRN were dramatically elevated in lesions of patients with psoriasis vulgaris. We also demonstrated that PGRN levels were significantly higher in serum of patients with psoriasis vulgaris than those of control subjects. In addition, serum PGRN concentrations in psoriasis vulgaris patients were significantly decreased after effective treatment. The levels of TNF-a and IL-6 in psoriasis vulgaris patients were up-regulated significantly compared with that of the normal controls. And there was a significant and positive correlation between serum PGRN and TNF-a levels in pre-treatment psoriasis vulgaris patients. However, there was no significant correlation between serum levels of PGRN and IL-6. Furthermore, the serum PGRN/ TNF-a ratio was negatively correlated with PASI scores.Repeated application of TPA to the ears of WT C57BL/6 mice induced progressive moderate psoriasis-like inflammation manifested by redness, scaling and thickening. Histology of TPA-treated ears in WT mice revealed acanthosis, formation of rete pegs, parakeratosis, formation of epidermal microabscesses, and thickening of the subepidermal layer with dense inflammatory cellular infiltrates. All these changes are highly characteristic of psoriasis lesions. Mouse model of psoriasis vulgaris was successfully established. PGRN expression was dramatically enhanced in the psoriasis-like lesions of TPA-treated WT mice, in accordance with human psoriatic lesions.Applying multiple topical TPA challenges in PGRN-/- mice and their WT counterparts, we found significantly stronger inflammatory response, manifested by more redness, thickening and scaling in PGRN-/- mice compared with WT mice. The ear samples were also assessed via histology and the result revealed that PGRN-/- mice exhibited thicker epithelium, larger epidermal microabscesses, and increased dermal angiogenesis and infiltration of inflammatory cells than WT mice. PGRN-/- mice were more sensitive to the development of TPA induced psoriasis-like inflammation. TPA-treated PGRN-/- mice had significantly lower percentages of Treg cells (CD4+CD25+FoxP3+) in the affected ears and draining cervical lymph nodes compared to TPA-treated WT mice. By contrast, there was no significant difference in the percentages of Thl (CD4+IFN-γ+), Th2 (CD4+IL-4+) and Th17 (CD4+IL-17+) cells in the ears and cervical lymph nodes between WT and PGRN-/- miceConclusion:Our study demonstrates that PGRN plays a protective role in the pathogenesis of psoriasis vulgaris partly by increasing the numbers of Treg cells. Serum PGRN/TNF-a ratio could be a useful biomarker for disease severity. The feedback increase of PGRN was not sufficient to neutralize the development of psoriasis vulgaris. It’s suggested that the applications of recombinant PGRN may be useful as therapies for psoriasis.