From Inflammation to Fibrosis: Novel Insights into the Roles of High Mobility Group Protein Box 1 in Schistosome-Induced Liver Damage.

Haoran Zhong,Rongxue Lv,Yamei Jin,Xiang Gui,Ling Hou

doi:10.3390/pathogens11030289

Abstract

Schistosomiasis is a chronic helminthic disease of both humans and animals and the second most prevalent parasitic disease after malaria. Through a complex migration process, schistosome eggs trapped in the liver can lead to the formation of granulomas and subsequent schistosome-induced liver damage, which results in high mortality and morbidity. Although praziquantel can eliminate mature worms and prevent egg deposition, effective drugs to reverse schistosome-induced liver damage are scarce. High mobility group box 1 (HMGB1) is a multifunctional cytokine contributing to liver injury, inflammation, and immune responses in schistosomiasis by binding to cell-surface Toll-like receptors and receptors for advanced glycation end products. HMGB1 is increased in the serum of patients with schistosomiasis and enables hepatic stellate cells to adopt a proliferative myofibroblast-like phenotype, which is crucial to schistosome-induced granuloma formation. Inhibition of HMGB1 was found to generate protective responses against fibrotic diseases in animal models. Clinically, HMGB1 presents a potential target for treatment of the chronic sequelae of schistosomiasis. Here, the pivotal role of HMGB1 in granuloma formation and schistosome-induced liver damage, as well the potential of HMGB1 as a therapeutic target, are discussed.

Highlights

Schistosomiasis, or bilharzia, is an infectious disease endemic in tropical areas of Asia, Africa, and South America affecting over 230 million individuals worldwide [1]
A recent report of High mobility group box 1 (HMGB1) in schistosome-induced liver fibrosis found that serum levels and relative mRNA expression of HMGB1 were significantly higher in the livers of the S. japonicum/S. mansoni-infection group, while the expression levels of the pro-inflammatory and fibrogenic cytokines IFN-γ, transforming growth factor (TGF)-β1, and IL-6 were reduced [19,20]
Based on the close relationship between HMGB1 and TGF-β1 and the phosphoinositide 3-kinase (PI3K)/AKT pathway in various fibrotic diseases, the HMGB1/TGF-β1 and HMGB1/receptor for advanced glycation end-products (RAGE)/PI3K/AKT pathways may have a synergistic effect in granuloma-associated liver fibrosis, little has been reported about any direct connections, such as whether upregulation of the TGF-β1/Smad pathway is mediated by the RAGE binding site of HMGB1

Summary

Introduction

Schistosomiasis, or bilharzia, is an infectious disease endemic in tropical areas of Asia, Africa, and South America affecting over 230 million individuals worldwide [1]. Inhibition of the translation and release of HMGB1 or blocking related signaling pathways via the HMGB1 receptor can protect against hepatic inflammation and fibrosis, suggesting that HMGB1 may be a vital factor in schistosome-induced liver disease as well as a potential therapeutic target [20,21,22]. The life cycles of S. japonicum, S. mansoni, and S. haematobium, the three main species of schistosomes that infect humans, slightly differ according to distinct egg-laying sites, as well as migration inside the host [45,46]. Unlike S. japonicum and S. mansoni, S. haematobium primarily migrates from the hepatic portal vein to the vesicle venous plexus surrounding the bladder and induces urinary schistosomiasis [5]. Unlike S. japonicum and S. mansoni, S. haematobium primarily migrates from the 5hoef-16 patic portal vein to the vesicle venous plexus surrounding the bladder and induces urinary schistosomiasis [5].

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HMGB1 and Schistosome-Induced Liver Damage

HMGB1 and Liver Inflammation

HMGB1 and Liver Fibrosis

Findings

Concluding Remarks