Galectin-3 Deficiency Facilitates TNF-α-Dependent Hepatocyte Death and Liver Inflammation in MCMV Infection

Abstract

Galectin-3 (Gal-3) has a role in multiple inflammatory pathways. Various, opposite roles of Gal-3 in liver diseases have been described but there are no data about the role of Gal-3 in development of hepatitis induced with cytomegalovirus infection. In this study we aimed to clarify the role of Gal-3 in murine cytomegalovirus (MCMV)-induced hepatitis by using Gal-3–deficient (Gal-3 KO) mice. Here we provide the evidence that Gal-3 has the protective role in MCMV-induced hepatitis. Enhanced hepatitis manifested by more inflammatory and necrotic foci and serum level of ALT, enhanced apoptosis and necroptosis of hepatocytes and enhanced viral replication were detected in MCMV-infected Gal-3 deficient mice. NK cells does not contribute to more severe liver damage in MCMV-infected Gal-3 KO mice. Enhanced expression of TNF-α in the hepatocytes of Gal-3 KO mice after MCMV infection, abrogated hepatocyte death, and attenuated inflammation in the livers of Gal-3 KO mice after TNF-α blockade suggest that TNF-α plays the role in enhanced disease in Gal-3 deficient animals. Treatment with recombinant Gal-3 reduces inflammation and especially necrosis of hepatocytes in the livers of MCMV-infected Gal-3 KO mice. Our data highlight the protective role of Gal-3 in MCMV-induced hepatitis by attenuation of TNF-α-mediated death of hepatocytes.

Galectin 3 protects from cisplatin-induced acute kidney injury by promoting TLR-2-dependent activation of IDO1/Kynurenine pathway in renal DCs

“…Administration of recombinant Gal-3 (rGal-3). In order to evaluate the effects of rGal-3 in attenuation of CDDP-induced AKI, Gal-3 -/- mice received single intravenous injection of rGal-3 (5 μg; Peprotech, Rocky Hill, NJ, United States), 24 h before CDDP administration 20. Gal-3 -/- animals from control group received only saline.…”

“…A large number of studies reported different (pro-or anti-inflammatory) role of Gal-3 in the development and progression of organ specific inflammatory diseases 12-17. Interestingly, use of different disease-causing agents may induce opposite Gal-3-dependent effects in the same tissue 18-20, suggesting that Gal-3-dependent effects are determined by etiological agents and inflammatory microenvironment of injured tissue. In persistent or repetitive kidney injury, overexpression of Gal-3 promotes apoptosis and collagen I synthesis in renal cells enhancing transition of acute to chronic inflammation and fibrosis 11.…”

A narrative review of the role of necroptosis in liver disease: a double-edged sword

“…Acute liver inflammation is usually induced by bacterial infection or physical and chemical injury. It is reported that higher necroptosis of hepatocytes emerged in Gal-3 deficient mice in acute CMV-induced liver disease (55). In patients suffering from drug-induced liver injury (DILI), cell death was demonstrated to be associated with activation of MLKL (56).…”

Galectin-3, Possible Role in Pathogenesis of Periodontal Diseases and Potential Therapeutic Target

“…Attenuated Th17 immune response and tissue damage in Gal-3 deficient mice has been also repoprted in mouse model of rheumatoid arthritis ( Forsman et al, 2011 ) and Concanavalin A induced acute inflammatory liver damage ( Volarevic et al, 2012 ). However, in PBC model induced by strong stimulation of immune system with antigen and adjuvant ( Arsenijevic et al, 2016 ), experimental autoimmune encephalomyelitis induced by immunization with MOG 35–55 peptide ( Jiang et al, 2009 ), multiple low dose streptozotocin-induced diabetes in mice ( Mensah-Brown et al, 2009 ), acute kidney injury induced by cisplatin ( Volarevic et al, 2019 ), and murine cytomegalovirus induced hepatitis ( Stojanovic et al, 2019 ) Gal-3 plays the protective role, attenuates Th1 and Th17 immune responses and tissue damage. In summary, Gal-3 may have double role in autoimmune processes, depending on the dominant pathogenic mechanisms involved ( Radosavljevic et al, 2012 ) and also could have the opposite effects on the outcome of the same disease, depending on the stage of disease which is most affected.…”