RT Journal Article
SR Electronic
T1 Heparan Sulfate-dependent RAGE oligomerization is indispensable for pathophysiological functions of RAGE
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.17.448852
DO 10.1101/2021.06.17.448852
A1 Miaomiao Li
A1 Chih Yean Ong
A1 Christophe J Langouët-Astrié
A1 Lisi Tan
A1 Ashwni Verma
A1 Yimu Yang
A1 Xiaoxiao Zhang
A1 Dhaval K. Shah
A1 Eric P. Schmidt
A1 Ding Xu
YR 2021
UL http://biorxiv.org/content/early/2021/08/04/2021.06.17.448852.abstract
AB 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 (RageAHA/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, RageAHA/AHA mice phenocopied Rage−/− 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 RageAHA/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 Rage−/− mice had a broad alteration of transcriptome in both tissues compared to wild-type mice, the changes of transcriptome in RageAHA/AHA mice were much more restricted. This unexpected finding suggests that by preserving the expression of RAGE protein (in a dominant-negative form), RageAHA/AHA mouse might represent a cleaner genetic model to study physiological roles of RAGE in vivo compared to Rage−/− mice.Competing Interest StatementThe authors have declared no competing interest.