Mannose receptor 1 mediates cellular uptake and endosomal delivery of CpG-motif containing oligodeoxynucleotides

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Toll-like receptor 9 (TLR9) activation by microbial DNA is essential for innate and adaptive immunity.
• TLR9 requires trafficking to endolysosomes and protease cleavage for activation by CpG oligodeoxynucleotides (ODNs).
• The mechanisms governing exogenous DNA uptake and the receptors involved are not fully understood.

Purpose of the Study:

• To investigate the genetic basis for hyporesponsiveness to CpG ODNs in wild-derived MOLF/Ei mice.
• To identify the specific gene responsible for impaired CpG ODN recognition and response.
• To elucidate the role of identified genes in the uptake and trafficking of exogenous DNA.

Main Methods:

• Genome-wide linkage analysis in N2 backcross mice.
• Phenotypic analysis of peritoneal macrophages from wild-derived mouse strains.
• Assessment of CpG ODN and bacterial DNA responsiveness.
• Investigation of mannose receptor 1 (MRC1) function in CpG ODN uptake and cytokine response.

Main Results:

• MOLF/Ei mice exhibit hyporesponsiveness to CpG ODNs but normal responsiveness to bacterial DNA.
• Genome-wide linkage analysis mapped the CpG ODN hyporesponsiveness trait to a locus containing Mrc1.
• Mannose receptor 1 (MRC1) was identified as critical for CpG ODN uptake and TLR9-mediated cytokine production in wild-derived macrophages.
• Other wild-derived mouse strains also require MRC1 for CpG-induced immune responses.

Conclusions:

• Mannose receptor 1 (MRC1) plays a novel role in mediating the uptake and trafficking of CpG ODNs for TLR9 activation.
• Synthetic CpG ODNs do not fully recapitulate the recognition of naturally derived microbial DNA.
• Wild-derived mouse models are indispensable for uncovering natural regulators of innate immune pathways.