ABSTRACT
Skin psoriasis is defined as receiving external stimulation to activate skin dendritic cells (DCs) which can release interleukin 23 (IL-23) to interlink the innate and adaptive immunity as well as induce T helper 17 (Th17) cell differentiation leading to elevated production of interleukin 17 (IL-17) for keratinocytes over production. This autoimmune loop in psoriasis pathogenesis is influenced by G protein-coupled receptor (GPCR) signalling transduction, and in particular, function of adhesion molecule GPR97 in psoriasis endures to be utterly addressed. In this research, our team allocated GPR97 depletion (GPR97-/-), GPR97 conditional depletion on dendritic cell (DC-cKO), and keratin 14-conditional knockout (K14-cKO) mice models to explore the function of GPR97 which influences keratinocytes and skin immunity. It was found that significantly aggravated psoriasis-like lesion in GPR97-/- mice. In addition, hyperproliferative keratinocytes as well as accumulation of DCs and Th17 cells were detected in imiquimod (IMQ)-induced GPR97-/- mice, which was consistent with the results in DC-cKO and K14-cKO psoriasis model. Additional investigations indicated that beclomethasone dipropionate (BDP), an agonist of GPR97, attenuated the psoriasis-like skin disease and restricted HaCaT cells abnormal proliferation as well as Th17 cells differentiation. Particularly, we found that level of NF-κB p65 was increased in GPR97-/- DCs and BDP could inhibit p65 activation in DCs. Role of GPR97 is indispensable and this adhesion receptor may affect immune cell enrichment and function in skin and alter keratinocytes proliferation as well as differentiation in psoriasis.
Subject(s)
Imiquimod , Interleukin-17 , Interleukin-23 , Keratinocytes , Mice, Knockout , Psoriasis , Receptors, G-Protein-Coupled , Signal Transduction , Th17 Cells , Animals , Psoriasis/chemically induced , Psoriasis/pathology , Psoriasis/genetics , Psoriasis/metabolism , Interleukin-17/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/deficiency , Mice , Keratinocytes/metabolism , Keratinocytes/pathology , Th17 Cells/immunology , Th17 Cells/metabolism , Interleukin-23/metabolism , Dendritic Cells/metabolism , Mice, Inbred C57BL , Humans , Disease Models, Animal , Skin/pathology , Skin/metabolismABSTRACT
Backgroud: Obstructive jaundice increases intestinal permeability, but the pathological mechanisms remain obscure, which results in debates about the necessity of performing preoperative biliary drainage in patients with obstructive jaundice. Mucin-2 (MUC2) and goblet cells regulated by bile acids play an important role in maintaining the function of intestinal mucosal barrier. The present study was to investigate the role of goblet cells and MUC2 in obstructive jaundice and evaluate the effect of biliary drainage on intestinal permeability. STUDY DESIGN: We enrolled patients with malignant biliary obstruction and controls. We also did animal studies with four groups of rats: sham operation, obstructive jaundice, internal biliary drainage, and external biliary drainage. Histopathological analysis, biochemical measurement, and electron microscopy examination were done on pertinent samples. RESULTS: Compared with the control group, the small intestinal mucosa was significantly damaged; goblet cells and MUC2 were significantly decreased and serum endotoxin level was significantly increased in patients and rats with obstructive jaundice. Biliary drainage, especially internal biliary drainage, significantly increased goblet cells and MUC2 and attenuated the damage of small intestinal mucosa. CONCLUSIONS: In obstructive jaundice condition, goblet cells and MUC2 were reduced which were involved in the damage of intestinal mucosa barrier; biliary drainage increased goblet cells and MUC2, repaired mucosa layer and restored the intestinal mucosa barrier function.