Schistosome Infection Improves Energy Metabolism Through Regulating The Expression Of Inflammatory Cytokines In Mice

Schistosomiasis japonica is an amphixenosis yet a worldwide parasitic disease.The main pathological mechanism is granuloma and its subsequent fibrosis caused by eggs.The Thl-type(IFN-y,IL-2,IL-12,TNF-α,IL-18)and Th2-type(IL-10,IL-13,IL-4,IL-5)cytokines play a crucial role in the formation of fibrosis in schistosomiasis japonica.Thl cytokines Is the key in the early granuloma.While and Th2 cytokines are involved in the late stages of the disease.Although The view that schistosomes are harmful to humans has been ingrained in people’s minds.ome studies have shown thatt could prevent the development of metabolic and autoimmune diseases.Metabolic syndromes(MetS),for instance,obesity,T2DM,hyperglycemia and IR have been become a world-concerned public health issue.Recent studies have shown that a large number of inflammatory factors are involved in the process of the MetS,such as tumor necrosis factor(TNF-a),interleukin(IL),C-reactive protein revealing that inflammation and metabolic syndrome has a close relationship.In 2015 a survey of Chinese population showed that 465 patients with previous schistosome infection(PSI)developed lower incidence of metabolic syndrome and complications compared to 1132 subjects without PSI.Another study stated that the insulin sensitivity of adipose tissue and liver in obese mice were improved by Schistosoma mansoni infection or egg antigens immunization.Therefore,we hypothesized that Schistosoma japonicum infection could also improve host insulin sensitivity in MetS.We established Schistosoma japonicum infection,PZQ treatment and SEA antigens immunization model with C57BL/6 and Leprdb/db male mice in order to explore the relationship among worm infection and host’s energy metabolism.The study was divided into three parts:(1)Establishment of chronic infection model with 10 Schistosoma japonicum cercariae in C57BL/6 mice.(2)Establishment of praziquantel(PZQ)treatment model at 6 weeks after S.japonicum infection in C57BL/6 mice.(3)Etablishment of SEA immunization model by intraperitoneal injection for six weeks in C57BL/6 and Leprdb/db mice.We used automatic biochemical analyzer to test serum alanine aminotransferase(ALT),aspartate aminotransferase(AST),total cholesterol(TC),triglyceride(TG),high-density lipoprotein cholesterol(HDL-C),and low-density lipoprotein cholesterol(LDL-C),HE staining to evaluate the degree of liver inflammation,and real-time fluorescent quantitative PCR to detect the transcription level of inflammatory cytokines and insulin sensitivity pathway related genes.Glucose tolerance test(IPGTT)and insulin tolerance test(IP ITT)were used to evaluate body insulin sensitivities.Enzyme-linked immunosorbent assay(ELISA)was applied to measure serum insulin concentration and Western-Blot to evaluate the protein expression of t-AKT and p-AKT.The main results of our studies were as follows:1.The results of IPGTT,IPITT and the mRNA expression of target genes in glucose and insulin pathway detected by real-time PCR showed that glucose tolerance and insulin sensitivity were significantly improved in S.japonicum infection group,PZQ treatment group and SEA immunization group.2.ELISA results demonstrated that compared with the control group,the insulin concentration in peripheral blood of C57BL/6-inf-12w group and C57BL/6-inf-PZQ-12w group were decreased significantly.3..The Western-Blot results of protein expression of t-AKT and p-AKT detected in the insulin-simulated infection liver in C57BL/6-inf model.It suggested that phosphorylated AKT protein expression and insulin signaling were both increased significantly.4.The results of lipid metabolism detected by automatic biochemical analyzer revealed that concentration of mice lipid in chronic infection group and PZQ treatment group are significantly lower thanthose in control group.5.The result of linear regression analysis of liver inflammation factor and insulin and glucose pathway target genes showed that:(1)In chronic infection model,IL-22 could up-regulate the expression of insulin-sensitive IRS-1 and INSR,while IL-33 could up-regulate the expression of IRS-2.Meanwhile IL-10,IL-22 and IL-33 could accelerate the glucose metabolism and reduce gluconeogenesis(2)In PZQ treatment model,IL-22 also up-regulated the expression of IRS-l so as to increase the insulin sensitivity.IL-13 can up-regulate the expression of GLUT4 to accelerate glucose metabolism.6.In SEA immunization group,the mRNA expression of TNF-a was almost unchanged,while the expression of anti-inflammatory cytokines such as IL-13 and IL-22 were significantly increased compared with the control group.SEA immunization might induce a dominant Th2 type response.7.In vitro results showed that TNF-a stimulation in murine hepatocytes line down-regulated the expression of IRS-1,IRS-2,INSR and GLUT4,while IL-22 and IL-13 could act as an anti-inflammatory cytokines to increase insulin sensitivity.In summary,the present study illustrated that the changes of inflammatory cytokines dynamically influence metabolism in the process of Schistosoma japonicum infection and SEA immunization.We found that Schistosoma japonicum infection and SEA immunization could possibly improve hepatic insulin sensitivity through regulating the expression of inflammatory cytokines in mice.