Echinococcus multilocularis drives the polarization of macrophages by regulating the RhoA-MAPK signaling pathway and thus affects liver fibrosis.

Echinococcus multilocularis is a small parasite that causes alveolar echinococcosis. It primarily induces liver disorder, such as liver fibrosis and even liver cancer, which severely endangers human lives. This study aims to explore the efficacy of Echinococcus multilocularis soluble antigen in preventing and alleviating alveolar echinococcosis-induced liver fibrosis and determine the underlying mechanism. We first identified the optimal dose and time of Echinococcus multilocularis soluble antigen. The protein levels of key genes in the RhoA-MAPK signaling pathway were remarkably upregulated in RAW264.7 and Ana-1 cells induced with 80 µg/mL Echinococcus multilocularis soluble antigen for 8 h. Interestingly, the upregulated expression levels were remarkably reversed by the RhoA, JNK, ERK, or p38 inhibitor, confirming the significance of the RhoA-MAPK signaling pathway. In addition, the relative contents of M2 polarization markers IL-10 and Arg-1 in macrophages induced with 80 µg/mL Echinococcus multilocularis soluble antigen for 8 h increased, whereas those of M1 polarization markers IL-12 and NOS-2 decreased. Mouse hepatic stellate cells were the key components of the hepatocellular carcinoma tumor microenvironment. Hepatic stellate cells were activated by Echinococcus multilocularis soluble antigen and transformed into the morphology of myofibroblasts in response to liver disorders. By detecting the marker of myofibroblast formation, RhoA inhibitor remarkably reduced the positive expression of α-SMA in mouse hepatic stellate cells induced with Echinococcus multilocularis soluble antigen. Therefore, Echinococcus multilocularis soluble antigen remarkably activated the RhoA-MAPK pathways in macrophages, further inducing the polarization of macrophages and ultimately causing liver fibrosis. HYPOTHESIS: We hypothesize that infection with Echinococcus multilocularis activates the RhoA-MAPK signaling pathway and subsequently induces macrophage polarization to promote hepatic stellate cells activation leading to liver fibrosis. AIMS: To investigate the mechanism by which soluble antigen of Echinococcus multilocularis affects liver fibrosis through the RhoA-MAPK pathway driving polarization of macrophages. GOALS: To identify new pathways of intervention and drug targets for the regulation of macrophage polarity phenotype switching and the attenuation or inhibition of the development and treatment of liver fibrosis caused by Echinococcus multilocularis infection.

Mechanism of Fibrosis Induced by Echinococcus spp.

Infection with Echinococcus spp. causes fibrosis in various vital organs, including the liver and lungs. Hepatic fibrosis is a pathological feature of Echinococcus infection that destroys normal liver tissue, leading to jaundice, cholecystitis, portal hypertension, etc. Severe Echinococcus multilocularis infections lead to liver failure and hepatic encephalopathy. The formation of peripheral fiberboards around the metacestode is a major reason as to why antiparasitic drugs fail to be effectively transported to the lesion site. Studies on the mechanism of hepatic fibrosis caused by Echinococcus are important for treatment in patients. Recent studies have focused on miRNA and TGF-ß. More recent findings have focused on the generation of collagen fibers around the metacestode. In this review paper we focus on the mechanism by which the Echinococcus parasite induces fibrosis in liver and some other organs in intermediate hosts-animals as well as human beings.

The MAPK Signaling Pathways as a Novel Way in Regulation and Treatment of Parasitic Diseases.

Few major advances in fighting parasitic diseases have been made in China since the development of new methods for prevention, control, and elimination. However, the proportion of immunocompromised individuals has increased due to the growth of chronic diseases, population aging, and more frequent cases of patients with AIDS and cancer. All these problems can promote development of parasitic infections, which is commonly associated with manipulation of host signaling pathways and the innate immune system. Mitogen-activated protein kinase (MAPK) signaling pathways are evolutionarily conserved in metazoan organisms, which play critical roles in the cell cycle, gene expression, growth, differentiation, apoptosis, and parasite⁻host interactions. Recent discoveries of the MAPK components involved in activation, regulation, and signal transduction appeared to be promising for the diagnosis, prevention, and treatment of parasitic diseases in the future. This review summarizes the involvement and critical role of the MAPK family in parasitic disease development and maintenance in the host. Moreover, it highlights recent studies concerning the mechanisms and novel drug development for inhibition and regulation of MAPK pathways in order to prevent parasitic disease. In addition, we discuss some antigenic proteins as prospective inhibitory molecules or vaccines for the regulation and control of MAPK signaling involved in parasite physiological activity.