The immunomodulatory quinoline-3-carboxamide paquinimod reverses established fibrosis in a novel mouse model for liver fibrosis

Abstract

Quinoline-3-carboxamides (Q substances) are small molecule compounds with anti-inflammatory properties. In this study, we used one of these substances, Paquinimod, to treat a novel model for chronic liver inflammation and liver fibrosis, the NOD-Inflammation Fibrosis (N-IF) mouse. We show that treatment of N-IF mice significantly reduced inflammation and resulted in the regression of fibrosis, even when the treatment was initiated after onset of disease. The reduced disease phenotype was associated with a systemic decrease in the number and reduced activation of disease-promoting transgenic natural killer T (NKT)-II cells and their type 2-cytokine expression profile. Paquinimod treatment also led to a reduction of CD115+ Ly6Chi monocytes and CD11b+ F4/80+ CD206+ macrophages.

NKT cells promote both type 1 and type 2 inflammatory responses in a mouse model of liver fibrosis

“…As previously described 33 the hydroxyproline content of the liver was determined using a hydroxyproline colorimetric assay kit (BioVision, Milpitas, CA, USA) according to the manufacturer’s instructions. Briefly, 100 μl of wet tissue (10 mg) was hydrolyzed in 100 μl of 12 N HCl for 3 h at 120 °C.…”

“…We have previously described a new model for liver fibrosis, the nonobese diabetic inflammation and fibrosis (NIF) mouse 33 , 34 , in which a transgenic NKT cell population induces chronic inflammation and fibrosis. Here, we demonstrate that, in this model, transgenic NKT cells drive a type 1 inflammatory response through the production of pro-inflammatory cytokines involving the activation of the NLRP3 inflammasome and promote the switch to a predominantly anti-inflammatory, reparative/profibrotic response through the production of type 2 cytokines such as IL-13.…”

S100A8/A9 modulates inflammatory collateral tissue damage during intraperitoneal origin systemic candidiasis

“…Thus, the reported effect on ICTD in an experimental model of IAC is, at least to a large proportion, dependent on S100A8/A9 and pharmacological targeting of the protein complex could be beneficial in patients with IAC. To demonstrate this, we used paquinimod; a compound applied for treatment of chronic inflammatory diseases (17,20). As paquinimod is a specific binder for S100A9 (40), it blocks the pro-inflammatory activity of the S100A8/A9 complex in vivo .…”

“…In addition to the antimicrobial benefit, S100A8/A9 is used in diagnostics to monitor neutrophil elevation in various inflammatory diseases (16). The q-compound paquinimod, an immunomodulatory compound that prevents the binding of S100A9 to TLR4, was designed to target chronic inflammatory S100A8/A9 dependent diseases (17–22). Using a murine peritonitis model with C. albicans , we show here that the inflammatory response failed to contain the pathogen in the peritoneum but instead led to detrimental ICTD dependent on the presence of S100A8/A9.…”

S100 proteins as therapeutic targets

“…Although current efforts are focused on improving the affinity, selectivity, and biological half-life of these S100 inhibitors, a number of these compounds have been evaluated in murine models of disease and some have advanced to human clinical trials. Paquinimod reduces inflammation and disease progression and/or severity in a number of inflammatory models (Fransen Pettersson et al 2018;Tahvili et al 2018;Wache et al 2015). Tasquinimod inhibits tumor growth and metastasis in several models of prostate cancer, possibly by limiting the recruitment of MDSCs and tumor-associated macrophages to the tumor microenvironment (Raymond et al 2014).…”