Polyguanine alleviated autoimmune hepatitis through regulation of macrophage receptor with collagenous structure and TLR4‐TRIF‐NF‐κB signalling

Abstract

Autoimmune hepatitis (AIH) is a progressive and chronic inflammatory disease in the liver. MARCO is a surface receptor of macrophage involving in tissue inflammation and immune disorders. Moreover, polyguanine (PolyG) is considered to bind to macrophage receptor with collagenous structure (MARCO). However, the role of MARCO and PolyG in the development and treatment of AIH still remains unclear. Therefore, this study explores the expression of MARCO and therapeutic activity of PolyG in both S100-induced AIH in mouse and Lipopolysaccharide (LPS)-treated macrophage (RAW264.7 cells). Moreover, there were significant increases in inflammatory factors and MARCO, as well as decrease in I-kappa-B-alpha (Ik-B) in the liver of AIH mice and LPS-induced cells. However, PolyG treatment significantly reversed the elevation of inflammatory cytokins, MARCO and reduction of Ik-B. In addition, PolyG treatment could downregulate the expression of Toll-like receptor 4 (TLR4) and TIR-domaincontaining adaptor inducing interferonβ (TRIF), decrease macrophage M1 polarization and increase macrophage M2 polarization. When hepatocytes were co-cultured with different treatment of macrophages, similar expression profile of inflammatory cytokines was observed in hepatocytes. The research revealed that MARCO expression was elevated in AIH mice. PolyG treatment and inhibition of MARCO significantly reduced inflammatory cytokines expression in the liver as well as hepatocytes and macrophages. Therefore, MARCO could be a target for the treatment of AIH.

TRIF-dependent signaling and its role in liver diseases

“…In recent years, an increasing number of studies have reported the pivotal role of TRIF in the pathogenesis of liver diseases ( Cai et al, 2009 ; Riad et al, 2011 ; Ayoobi et al, 2013 ; Chen et al, 2017 ; Cai et al, 2022 ). Interestingly, TRIF exhibits diverse functions in various liver conditions, impacting both steatosis and inflammation.…”

“…However, TRIF knockout aggravates hepatic steatosis in a HFD-fed mouse model by enhancing SCD1 transcription and promoting lipid synthesis, suggesting a context-dependent inhibitory role in this model ( Chen et al, 2017 ). Similarly, TRIF can facilitate liver inflammation progression through IRF3 and NF-κB signaling pathways in ALD and AIH models, respectively ( Zhao et al, 2008 ; Cai et al, 2022 ). Furthermore, TRIF knockout in a hepatic IRI model resulted in reduced expression of inflammatory factors such as IL-6 and IL-1β in the liver ( Zhai et al, 2004 ).…”

“…Additionally, they found a significant increase in the mRNA and protein expression levels of liver TNF-α and NF-κB, while the expression levels of I-κB mRNA and protein were decreased. Their findings suggest that liver S100 atigen activates TLR4-TRIF-NF-κB signaling pathway to induce AIH in mice ( Cai et al, 2022 ). However, their study did not investigate the role of TRIF whole-body knockout or hepatocyte-specific TRIF knockout in the AIH mouse models for further validation.…”

“…The dysregulation of TNF-α in macrophages induced by chronic alcohol exposure highly depends on the TRIF-IRF3 pathway ( Zhao et al, 2008 ). In a mouse model of AIH, it was found that TLR4 sequentially activates TRIF and NF-κB, thus accelerating inflammatory responses ( Cai et al, 2022 ). In these aforementioned models, TRIF acts as a promoter of liver inflammation.…”

Macrophage polarization: an important role in inflammatory diseases

“…A potential therapeutic target for AIH is Receptor-interacting protein kinase 3 (RIP3), which can contribute to macrophage activation in AIH and promote IL-6 production, in addition, enhancer of zeste homolog 2 (EZH2) -mediated H3K27me3 may also influence the progression of AIH by modulating the polarization of macrophages, EZH2 is also promising as a therapeutic target ( 79 , 80 ). Furthermore, studies have shown that polyguanine (PolyG) can bind to macrophage receptors with collagen structure(MARCO), and that polyG therapy can regulate MARCO, reduce M1-like macrophage polarization, and increase M2-like macrophage polarization, thereby linking AIH, MARCO can also become a target for AIH treatment ( 81 ). Interleukin is a frequent cytokine associated with a variety of diseases.…”