Tissue Transglutaminase‐Regulated Transformed Growth Factor‐β1 in the Parasite Links Schistosoma japonicum Infection with Liver Fibrosis

Abstract

Transforming growth factor (TGF-β1) is among the strongest factors of liver fibrogenesis, but its association with Schistosoma-caused liver fibrosis is controversial. Tissue transglutaminase (tTG) is the principal enzyme controlling TGF-β1 maturation and contributes to Sj-infected liver fibrosis. Here we aim to explore the consistency between tTG and TGF-β1 and TGF-β1 source and its correlation with liver fibrosis after Sj-infection. TGF-β1 was upregulated at weeks 6 and 8 upon liver fibrosis induction. During tTG inhibition, TGF-β1 level decreased in sera and liver of infected mice. TGF-β1 showed positive staining in liver containing Sj adult worms and eggs. TGF-β1 was also detected in Sj adult worm sections, soluble egg antigen and Sj adult worm antigen, and adult worms' culture medium. The TGF-β1 mature peptide cDNA sequence and its extended sequence were amplified through RT-PCR and RACE-PCR using adult worms as template, and sequence is analyzed and loaded to NCBI GenBank (number GQ338152.1). TGF-β1 transcript in Sj eggs was higher than in adult worms. In Sj-infected liver, transcriptional level of TGF-β1 from Sj, but not mouse liver, correlated with liver fibrosis extent. This study provides evidence that tTG regulates TGF-β1 and illustrates the importance of targeting tTG in treating Sj infection-induced fibrosis.

Positive Feedback Regulation between Transglutaminase 2 and Toll-Like Receptor 4 Signaling in Hepatic Stellate Cells Correlates with Liver Fibrosis Post Schistosoma japonicum Infection

“…The expression of α-SMA, COL I, and COL III was moderate at week 8 after Sj infection (Figure 1 C, right ). Consistent with the results of our previous study ( 19 , 20 ), liver granuloma induced by Sj infection began at week 5, acute fibrosis began at week 6, and advanced liver fibrosis began at week 8. The areas of collagen deposition and the expressions of α-SMA, COL I, and COL III all decreased at week 12 (chronic liver fibrosis).…”

“…Our previous work indicated that TGM2 contributes to liver fibrosis post Sj infection ( 19 , 20 ). Thus, both TGM2 and activation of the TLR4 signal pathway correlated with the development of liver fibrosis during Sj infection.…”

“…Transglutaminase 2 (TG2 or TGM2), also known as tissue transglutaminase, is a multifunctional enzyme involved in several important biological processes, including cell death, signaling, cytoskeleton rearrangements, ECM stabilization, and fibrosis ( 17 , 18 ). We have provided evidence that TGM2 regulates the TGF-β1 of parasite origin and IL-13 of the host as well as documented the important role of TGM2 in liver fibrosis during Sj infection ( 19 , 20 ). Tgm2 expression has been reported to be induced by LPS in macrophages, microglial cells, and astrocytes ( 21 – 23 ).…”

Corilagin controls post-parasiticide schistosome egg-induced liver fibrosis by inhibiting Stat6 signalling pathway

“…Chronic Schistosoma infection is one of the known aetiologies leading to liver fibrosis. Schistosomiasis is a major neglected tropical infectious disease that has serious public health consequences (54). In China, schistosomiasis japonica is a major health risk for more than 50 million people (55).…”

Transglutaminase 2 in human diseases

“…As a result, TGF-β drives TG2 expression, while TG2 contributes to the transcription, secretion and activation of TGF-β leading to the formation of an additional level of self-amplification loop in the pathogenesis of fibrosis. Not surprisingly, fibroproliferative diseases are characterized not only by enhanced TGF-β production, but also by enhanced TG2 expression [ 41 , 42 ]. The central role of TG2 in maintaining these diseases is proven by the observation that TG2 knock out mice are protected from fibrosis in several experimental fibrosis models [ 43 , 44 ].…”