title: Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis.
abstract: We recently reported that abundant deposits of the extracellular matrix polysaccharide hyaluronan (HA) are characteristic of autoimmune insulitis in patients with type 1 diabetes (T1D), but the relevance of these deposits to disease was unclear. Here, we have demonstrated that HA is critical for the pathogenesis of autoimmune diabetes. Using the DO11.10xRIPmOVA mouse model of T1D, we determined that HA deposits are temporally and anatomically associated with the development of insulitis. Moreover, treatment with an inhibitor of HA synthesis, 4-methylumbelliferone (4-MU), halted progression to diabetes even after the onset of insulitis. Similar effects were seen in the NOD mouse model, and in these mice, 1 week of treatment was sufficient to prevent subsequent diabetes. 4-MU reduced HA accumulation, constrained effector T cells to nondestructive insulitis, and increased numbers of intraislet FOXP3+ Tregs. Consistent with the observed effects of 4-MU treatment, Treg differentiation was inhibited by HA and anti-CD44 antibodies and rescued by 4-MU in an ERK1/2-dependent manner. These data may explain how peripheral immune tolerance is impaired in tissues under autoimmune attack, including islets in T1D. We propose that 4-MU, already an approved drug used to treat biliary spasm, could be repurposed to prevent, and possibly treat, T1D in at-risk individuals.
authors.forename: Nadine
authors.initials: N
authors.lastname: Nagy
authors.forename: Gernot
authors.initials: G
authors.lastname: Kaber
authors.forename: Pamela Y
authors.initials: PY
authors.lastname: Johnson
authors.forename: John A
authors.initials: JA
authors.lastname: Gebe
authors.forename: Anton
authors.initials: A
authors.lastname: Preisinger
authors.forename: Ben A
authors.initials: BA
authors.lastname: Falk
authors.forename: Vivekananda G
authors.initials: VG
authors.lastname: Sunkari
authors.forename: Michel D
authors.initials: MD
authors.lastname: Gooden
authors.forename: Robert B
authors.initials: RB
authors.lastname: Vernon
authors.forename: Marika
authors.initials: M
authors.lastname: Bogdani
authors.forename: Hedwich F
authors.initials: HF
authors.lastname: Kuipers
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Day
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Campbell
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Wight
authors.forename: Paul L
authors.initials: PL
authors.lastname: Bollyky
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology; D006820:Hyaluronic Acid / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006923:Hymecromone / Q000494:pharmacology / Q000627:therapeutic use*; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D007108:Immune Tolerance / Q000187:drug effects*; D007328:Insulin / Q000096:biosynthesis; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011236:Prediabetic State / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D054411:Receptors, Leptin / Q000172:deficiency; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: C476399:Cd44 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018960:Hyaluronan Receptors; D007328:Insulin; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D006923:Hymecromone; D006820:Hyaluronic Acid