Heparan sulfate in Inflammation
Another main focus of the lab is to understand the biological role of HS in inflammation. The functions of HS in inflammation is well known and highly diverse. This is hardly surprising because inflamed tissue is filled with HS-binding proteins including chemokines, cytokines, coagulating factors, growth factors, adhesion molecules and various cell surface receptors. By understanding the details of how individual inflammatory proteins interact with HS and how HS regulates their activity, we expect to modulate the activity of these proteins in inflammation, which might lead to novel therapeutics.
Current work in the lab mainly focuses on the role of HS in regulating two key inflammatory mediators: HMGB1 and its receptor RAGE. HMGB1 is a founding member of the damage-associated molecular patterns (DAMPs), which is often secreted by necrotic tissue and can function as both cytokine and chemokine.
HMGB1 has been associated with many inflammatory conditions such as sepsis, drug-induced liver injury, acute lung injury, ischemia-reperfusion injury and cancer. RAGE is a single transmembrane receptor that binds a diverse group of inflammatory mediators. In addition to HMGB1, it also binds advanced glycation endproducts (AGE), S100 family proteins, and amyloid beta. Because its hyperactivation is associated with atherosclerosis, sepsis, cancer, acute lung injury and Alzheimer disease, RAGE is being pursued as an attractive drug target. Both HMGB1 and RAGE are HS-binding proteins and our lab has done seminal works in establishing the structural details of their interactions with HS. Based on these structural studies, we further demonstrated the physiological significance of HMGB1–HS and RAGE-HS interactions in drug-induced liver injury and endothelial inflammation.
Currently, we are developing new projects trying to elucidate the roles of HS-HMGB1 and HS-RAGE interactions in acute respiratory distress syndrome and sepsis.
Key publications on Inflammation:
Miaomiao Li, Chih Yean Ong, Christophe J Langouët-Astrié, Lisi Tan, Ashwni Verma, Yimu Yang, Xiaoxiao Zhang, Dhaval K. Shah, Eric P. Schmidt and Ding Xu (2022). Heparan Sulfate-dependent RAGE oligomerization is indispensable for pathophysiological functions of RAGE. eLife (2022);11:e71403 DOI: 10.7554/eLife.71403.
Arnold K, Xu Y, Sparkenbaugh EM, Li M, Han X, Zhang X, Xia K, Piegore M, Zhang F, Zhang X, Henderson M, Pagadala V, Su G, Tan L, Park PW, Stravitz RT, Key NS, Linhardt RJ, Pawlinski R, Xu D# and Liu J#. Design of anti-inflammatory heparan sulfate to protect against acetaminophen-induced acute liver failure. Science Transl Med (2020). Mar 18;12(535). PMID 32188725 . #corresponding authors
Zhang X, Ong C, Su G, Liu J, Xu D. Characterization and Engineering of S100A12–Heparan sulfate interactions. Glycobiology. (2020) doi: 10.1093/glycob/cwz111. PMID: 31942981
Xu D, Young JH, Krahn JM, Song D, Corbett KD, Chazin WJ, Pedersen LC, Esko JD. Stable RAGE-heparan sulfate complexes are essential for signal transduction. ACS Chem Biol. 2013 Jul 19;8(7):1611-20. PMID: 23679870
Xu D, Young J, Song D, Esko JD. Heparan sulfate is essential for high mobility group protein 1 (HMGB1) signaling by the receptor for advanced glycation end products (RAGE). J Biol Chem. 2011 Dec 2;286(48):41736-44. PMID:21990362