Genetic analysis of the CpG hyporesponsiveness in wild-derived MOLF/Ei mice (158.16)

Abstract

Abstract CpG motif containing oligonucleotides are used to mimic the immunostimulatory properties of bacterial DNA in both innate and adaptive immune cells through the activation of toll-like receptor 9. Macrophages are one of the main cell types activated to elicit a pro-inflammatory response to CpG DNA. Downstream signaling of TLR9 is more well characterized and studied compared to upstreams events which remains largely unknown, such as what receptors and mechanisms are involved in CpG DNA receptor-mediated endocytosis and trafficking into endosomal compartments. While all classical laboratory mouse strains are responsive to CpG DNA activation a wild-derived inbred mouse strain, MOLF/Ei, is non-responsive. In this study we have used a forward genetics approach to analyze the CpG response in peritoneal macrophages from panels of N2 backcross mice [MOLF/Ei x (C57BL/6xMOLF/Ei)]. Our genome-wide linkage studies implicate, for the first time, the role of the mannose receptor, C type 1 (Mrc1) in the CpG hypo-responsiveness in MOLF/Ei mice. Furthermore, additional mapping studies have revealed a second receptor that is also involved in CpG DNA signaling for both classical and wild-derived mouse strains, implicating its role in CpG activation for the first time.