Inhibition of CCl4-induced liver inflammation and fibrosis by a NEU3 inhibitor.

Sialic acids are located on the ends of many glycoconjugates and are cleaved off by enzymes called sialidases (neuraminidases). Upregulation of neuraminidase 3 (NEU3) is associated with intestinal inflammation and colitis, neuroinflammation, and lung fibrosis. Genetic ablation of NEU3 or pharmacological inhibition of NEU3 reduces lung fibrosis in mice. To determine if inhibiting NEU3 can inhibit liver fibrosis in the commonly-used CCl4 model, in this report, we examined the effects of injections of the NEU3 inhibitor 2-acetyl pyridine (2AP). 2AP inhibited CCl4-induced weight loss in female but not male mice. 2AP attenuated CCl4-induced liver inflammation and fibrosis in male and female mice, but did not affect CCl4-induced steatosis. After CCl4 treatment, female but not male mice had significant increases in liver neutrophils, and 2AP attenuated this response. 2AP also reversed CCl4-induced liver desialylation and CCl4-induced increased expression of NEU3. Patients with pulmonary fibrosis have increased desialylation of some serum proteins, and elevated serum levels of NEU3. We find that sera from patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have elevated desialylation of a serum protein and patients with NAFLD have increased levels of NEU3. These data suggest that elevated levels of NEU3 may be associated with liver inflammation and fibrosis, and that in mice this is ameliorated by injections of a NEU3 inhibitor.
Competing Interests: RHG is a scientific founder of Prosia Therapies, an early-stage company developing NEU3 inhibitors as therapeutics for pulmonary fibrosis. Texas A&M University has published patent applications on the use of sialidase inhibitors (United States Patent Application 20190201485) to regulate fibrosis. DP and RHG are inventors on pending patent applications for the use of sialidase inhibitors as anti-inflammatory, anti-fibrotic, and/or anti-obesity compounds.
(Copyright: © 2024 Pilling et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)