The Brand New Resiquimod Is Twice The Fun

We think HA fits in that category and will function to heighten innate defenses. Acknowledgment The authors are supported by NIH Grants HD061918 and HL17147 (to Carol A. de la Motte). Conflict of Interests The authors declare that they have no conflict of interests regarding the publication of this paper.""Stabilin-2 (Stab2) and HARE (half-length Stab2) function as primary scavenger receptors for the systemic clearance from lymph and blood of hyaluronan (HA) [1], heparin (Hep), and 12 other functionally and structurally distinct ligands [2�C6]. HA turnover and catabolism by HARE have been studied extensively for decades [1, 7, 8] and the responsible receptor was molecularly Resiquimod identified >15 years ago after it was purified and cloned [5, 6, 9, 10]. HARE endocytosis of HA occurs over a broad range of sizes from ~2.5?kDa to >MDa [11]. Hep is cleared from the body by two different mechanisms: larger Hep is rapidly cleared from blood in a high-affinity saturable binding mechanism by HARE/Stab2 in liver sinusoidal endothelial cells [12, 13], whereas low mass Hep is primarily cleared by kidney [14] in a nonsaturable renal excretion mechanism [15]. HA and Hep have distinct binding sites within the HARE ectodomain and neither LEE011 order ligand competes for the binding and endocytosis of the other [2]. Several articles in this special issue summarize the many functions of HA. As with HA, the biological and clinical activities of Hep have been studied for decades, and Hep is the most highly prescribed drug in the USA (e.g., for preventing or treating thromboembolic diseases and postsurgery clotting) [16]. HA is synthesized by many cell types and is the longest (up to 5 �� 104 sugars) and only unsulfated glycosaminoglycan. In contrast, Hep is synthesized by mast cells as a serglycin proteoglycan with much shorter polysaccharide chains, SAR405838 in vivo disaccharide isomers and binds to many different matrix, soluble, and cell surface proteins, including growth factors [19]. Hep also functions as a coreceptor or anticoagulant agent [20, 21]. Many receptors require bound ligand in order to interact with adapter proteins and then be targeted to coated pits [22]. In contrast, HARE and other constitutively recycling clearance receptors (e.g., asialoglycoprotein and LDL receptors) are continuously targeted to coated pits, internalized, and recycled back to the cell surface whether bound to ligand or not. Endocytic receptors often contain a tyrosine-based motif (e.g., YXX�� or NPXY, where X is any amino acid and �� is a hydrophobic residue) or a dileucine motif (D/EXXXLL/I) involved in clathrin-mediated endocytosis [23�C26].