title: Hyaluronan anchored to activated CD44 on central nervous system vascular endothelial cells promotes lymphocyte extravasation in experimental autoimmune encephalomyelitis.
abstract: The extravasation of lymphocytes across central nervous system (CNS) vascular endothelium is a key step in inflammatory demyelinating diseases including multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). The glycosaminoglycan hyaluronan (HA) and its receptor, CD44, have been implicated in this process but their precise roles are unclear. We find that CD44(-/-) mice have a delayed onset of EAE compared with wild type animals. Using an in vitro lymphocyte rolling assay, we find that fewer slow rolling (<1 μm/s) wild type (WT) activated lymphocytes interact with CD44(-/-) brain vascular endothelial cells (ECs) than with WT ECs. We also find that CD44(-/-) ECs fail to anchor HA to their surfaces, and that slow rolling lymphocyte interactions with WT ECs are inhibited when the ECs are treated with a pegylated form of the PH20 hyaluronidase (PEG-PH20). Subcutaneous injection of PEG-PH20 delays the onset of EAE symptoms by ~1 day and transiently ameliorates symptoms for 2 days following disease onset. These improved symptoms correspond histologically to degradation of HA in the lumen of CNS blood vessels, decreased demyelination, and impaired CD4(+) T-cell extravasation. Collectively these data suggest that HA tethered to CD44 on CNS ECs is critical for the extravasation of activated T cells into the CNS providing new insight into the mechanisms promoting inflammatory demyelinating disease.
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA.
authors.forename: Clayton W
authors.initials: CW
authors.lastname: Winkler
authors.forename: Scott C
authors.initials: SC
authors.lastname: Foster
authors.forename: Steven G
authors.initials: SG
authors.lastname: Matsumoto
authors.forename: Marnie A
authors.initials: MA
authors.lastname: Preston
authors.forename: Rubing
authors.initials: R
authors.lastname: Xing
authors.forename: Bruce F
authors.initials: BF
authors.lastname: Bebo
authors.forename: Fatima
authors.initials: F
authors.lastname: Banine
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Berny-Lang
authors.forename: Asako
authors.initials: A
authors.lastname: Itakura
authors.forename: Owen J T
authors.initials: OJ
authors.lastname: McCarty
authors.forename: Larry S
authors.initials: LS
authors.lastname: Sherman
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology*; D005091:Exons; D005260:Female; D018960:Hyaluronan Receptors / Q000096:biosynthesis* / Q000235:genetics; D006820:Hyaluronic Acid / Q000737:chemistry*; D007249:Inflammation; D036904:Leukocyte Rolling; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid