NASH Target Development Service for CXCR3

The non-alcoholic steatohepatitis (NASH) is featured by the presence of an abnormal accumulation of fat in the liver which can progress to inflammation and liver cell injury (hepatocellular ballooning) in some individuals. Chemokines and their receptors regulate the infiltration of immune cells to inflammatory sites, which takes a crucial part in both acute and chronic liver diseases. As a professional service supplier, Creative Biolabs is committed to providing the most robust target discovery, structural characterization, and functional analysis strategies for promising small molecule drugs. As well, chemokine receptor antagonists have already been applied in clinical trials and we could help clients to develop CXCR3 antagonists for NASH therapy.

Introduction of CXCR3

CXCR3 (CXC chemokine receptor 3), also known as CD183, CKR-L2, G protein-coupled receptor 9 (GPR9), interferon-inducible protein 10 receptor (IP10-R), and Mig receptor (Mig-R), is a seven transmembrane G-protein coupled receptor, which is highly expressed in activated T cells, monocytes/macrophages and resident cells (e.g. Kupffer cells, hepatocytes and hepatic stellate cells). It is a shared receptor for three CXC chemokines induced by IFN-γ, including CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC). These ligands bind to specific and distinct regions within the CXCR3 receptor. Recent studies suggested that CXCR3 plays a role in the migration of T cells in the microenvironment of the lymphoid compartments and peripheral tissues, facilitating the interaction between T cells and antigen presenting cells, thus leading to the generation of effector and memory cells. It is believed to be critical to promote inflammatory cell infiltration, lipid accumulation, and endoplasmic reticulum (ER) stress in the development of steatohepatitis.

Fig.1 Chemokine receptor CXCR3 and its ligands CXCL9, CXCL10, and CXCL11. (Michlmayr, 2014)

The Role of CXCR3 in NASH

Non-alcoholic fatty liver disease (NAFLD), and its pathologically more severe form NASH, have a global distribution paralleled with a rapidly increasing incidence of metabolic syndrome. Chemokines and their receptors have been considered the lynchpin in the transition of simple steatosis to steatohepatitis. CXCR3 has been verified that is involved in virus-related chronic liver inflammation and HCV infection. Therefore, elucidating the effect of CXCR3 on steatohepatitis may enable the development of novel pharmacological treatments for NASH.

One study examined the role of CXCR3 in NASH and evaluated the therapeutic efficacy of CXCR3 antagonists for the treatment of steatohepatitis. The results demonstrated that CXCR3 was largely upregulated in the liver tissue of NAFLD patients and in diet-induced NASH animal models. Compared with wild type (WT) littermates, CXCR3 knockout (CXCR3 (-/-)) mice were more resistant to both methionine-and-choline-deficient (MCD) diet and high-fat high-carbohydrate high-cholesterol (HFHC) diet-induced steatohepatitis models. Induction of CXCR3 in diet-induced steatohepatitis was correlated with the increased expression level of hepatic pro-inflammatory cytokines, activation of NF-κB, macrophage infiltration and T cell accumulation (Th1 and Th17 immune response). CXCR3 was also linked to steatosis via inducing hepatic lipogenic genes.

Fig.2 Schematic diagram for the mechanisms of CXCR3 in the promotion of dietary steatohepatitis. (Zhang, 2016)

Antagonist Developments at Creative Biolabs

Chemokines and corresponding receptors play critical roles in inflammatory conditions and might be the key in the transition of simple steatosis to NASH. Chemokine receptors have gained more attention as a potential target for new therapeutics. CXCR3 is responsible for T cell trafficking and functions, and exerts a pivotal role in NASH development by promoting inflammation, fatty acid synthesis, as well as causing ER stress and autophagy deficiency. Hence, pharmacologic blockade of CXCR3 is a valuable novel approach for NASH treatment. At Creative Biolabs, we’ re capable of offering the discovery, development, and production of CXCR5 antagonist to support the most effective viewpoint for improving NASH patients’ selection.

As a seasoned expert in small molecular discovery fields, Creative Biolabs has won high reputation worldwide for achieving various challenging projects regarding disease target development. Our collaborative strategies and deep scientific understanding of all biological fields help us shape flexible and optimal solutions to meet the needs of clients precisely. Besides, we also establish high-quality antibody development platforms, including Phage Display & Antibody Library Services, Antibody Analysis Services, and Antibody Engineering Services to manufacture therapeutic antibodies for different diseases. If you’re interested in our NASH-related services, please feel free to contact us for more details.

References

1. Michlmayr, D.; et al. Role of CXCL10 in central nervous system inflammation. IJICMR. 2014, 6: 1-18.
2. Zhang, X.; et al. CXC chemokine receptor 3 promotes steatohepatitis in mice through mediating inflammatory cytokines, macrophages and autophagy. J Hepatol. 2016, 64(1): 160-170.