huIL6/hIL6RA/Apoe-KO Mouse

Interleukin-6 (IL-6) is a cytokine that plays a crucial role in inflammation and B cell maturation. It is primarily produced and secreted into the serum at sites of acute and chronic inflammation, inducing inflammatory responses through the interleukin-6 receptor alpha (IL-6Rα). The IL6RA (IL6R, also known as CD126) gene encodes a subunit of the interleukin-6 (IL-6) receptor complex. The IL-6 receptor is a protein complex composed of the IL6RA protein and the interleukin-6 signal transducer (IL6ST/GP130/IL6-beta). This receptor subunit is shared by many other cytokines. The expression of IL-6R is primarily restricted to hepatocytes, leukocytes, and megakaryocytes. Upon binding to IL-6Rα, IL-6 interacts with two GP130 molecules to form a hexameric complex in a 2:2:2 configuration ^[1]. Once the IL-6 receptor complex is activated, multiple downstream events allow IL-6 to mediate its diverse effects. These include the pathways of the GTPase Ras and its effector Raf, the mitogen-activated protein kinase cascade that controls cellular proliferation and differentiation, and the pathways involving tyrosine kinases of the Jak family and transcription factors of the STAT family ^[2].

Apolipoprotein E (ApoE) is a lipid particle-associated polymorphic carrier protein encoded by the APOE gene. It is a core component of plasma lipoproteins, participating in the production, transport, and clearance of lipoproteins. ApoE is associated with chylomicrons, chylomicron remnants, high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL), especially showing preferential binding to HDL ^[3]. ApoE is the most important lipid transport protein in the body, having a profound impact on lipid metabolism. The interaction of ApoE with the low-density lipoprotein receptor (LDLR) is essential for the normal processing (catabolism) of triglyceride-rich lipoproteins ^[4]. In peripheral tissues, ApoE is primarily produced by the liver and macrophages and mediates cholesterol metabolism. In the central nervous system, ApoE is produced mainly by astrocytes and is the major cholesterol carrier in the brain. ApoE is essential for transporting cholesterol from astrocytes to neurons ^[3-6]. In addition, ApoE forms a complex with activated C1q, becoming a checkpoint inhibitor target of the classical complement pathway ^[7].

The huIL6/hIL6RA/Apoe-KO mouse is a combined genetically modified model generated by crossing the huIL6 mouse (Catalog No.: C001605), the hIL6RA mouse (Catalog No.: C001606), and the Apoe-KO(6J) mouse (Catalog No.: C001507). The huIL6/hIL6RA/Apoe-KO mouse can be utilized for the screening, pharmacodynamic evaluation, safety assessment, and mechanism of action studies of IL6/IL6RA-targeted therapeutics. With the Apoe knockout background, the model can also be used for research on hypercholesterolemia and atherosclerosis, providing a preclinical research tool for exploring the effects of IL6/IL6RA-targeted interventions in relevant disease settings.