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RAGE, a druggable inflammatory receptor, is known to function as an oligomer but the exact oligomerization mechanism remains poorly understood. Previously we have shown that heparan sulfate (HS) plays an active role in RAGE oligomerization. To understand the physiological significance of HS-induced RAGE oligomerization in vivo, we generated RAGE knock-in mice ( Ager  AHA/AHA ) by introducing point mutations to specifically disrupt HS-RAGE interaction. The RAGE mutant demonstrated normal ligand-binding but impaired capacity of HS-binding and oligomerization. Remarkably,  Ager  AHA/AHA  mice phenocopied  Ager  −/−  mice in two different pathophysiological processes, namely bone remodeling and neutrophil-mediated liver injury, which demonstrates that HS-induced RAGE oligomerization is essential for RAGE signaling. Our findings suggest that it should be possible to block RAGE signaling by inhibiting HS-RAGE interaction. To test this, we generated a monoclonal antibody that targets the HS-binding site of RAGE. This antibody blocks RAGE signaling in vitro and in vivo, recapitulating the phenotype of  Ager  AHA/AHA  mice. By inhibiting HS-RAGE interaction genetically and pharmacologically, our work validated an alternative strategy to antagonize RAGE. Finally, we have performed RNA-seq analysis of neutrophils and lungs and found that while  Ager  −/−  mice had a broad alteration of transcriptome in both tissues compared to wild-type mice, the changes of transcriptome in  Ager  AHA/AHA  mice were much more restricted. This unexpected finding suggests that by preserving the expression of RAGE protein (in a dominant-negative form),  Ager  AHA/AHA  mouse might represent a cleaner genetic model to study physiological roles of RAGE in vivo compared to  Ager  −/−  mice.

Heparan sulfate-dependent RAGE oligomerization is indispensable for pathophysiological functions of RAGE