Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis
Nadine Nagy, Gernot Kaber, Pamela Y. Johnson, John A. Gebe, Anton Preisinger, Ben A. Falk, Vivekananda G. Sunkari, Michel D. Gooden, Robert B. Vernon, Marika Bogdani, Hedwich F. Kuipers, Anthony J. Day, Daniel J. Campbell, Thomas N. Wight, Paul L. Bollyky
Nadine Nagy, Gernot Kaber, Pamela Y. Johnson, John A. Gebe, Anton Preisinger, Ben A. Falk, Vivekananda G. Sunkari, Michel D. Gooden, Robert B. Vernon, Marika Bogdani, Hedwich F. Kuipers, Anthony J. Day, Daniel J. Campbell, Thomas N. Wight, Paul L. Bollyky
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Research Article Immunology

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

Nadine Nagy, Gernot Kaber, Pamela Y. Johnson, John A. Gebe, Anton Preisinger, Ben A. Falk, Vivekananda G. Sunkari, Michel D. Gooden, Robert B. Vernon, Marika Bogdani, Hedwich F. Kuipers, Anthony J. Day, Daniel J. Campbell, Thomas N. Wight, Paul L. Bollyky

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Figure 8

4-MU treatment relieves CD44-mediated inhibition of FOXP3 induction.

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4-MU treatment relieves CD44-mediated inhibition of FOXP3 induction. (A)...
(A) Percentage of GFP/FOXP3+ Tregs of total CD4+ T cells in BALB/c mice fed 4-MU or control chow for 2 weeks (n = 5–6 mice per group). (B) In vivo induction of FOXP3+ Tregs assessed 4 days after transfer of GFP/FOXP3–CD4+ T cells into Rag–/– hosts given 4-MU or control chow (n = 3 Rag–/– recipient animals). Data are from the spleens of recipient animals. (C) CD25 and FOXP3 expression by CD4+GFP/FOXP3– T cells activated for 72 hours with or without plate-bound HA or anti-CD44 antibody. (D) Pooled data for 3 independent experimental replicates for the representative data in C. (E) FOXP3 induction using Cd44+/+, Cd44–/+, or Cd44–/– precursors. (F) Pooled data for 3 independent experimental replicates for the representative data in E. (G) In vivo induction of FOXP3 assessed using cotransfer of equivalent numbers of GFP/FOXP3–CD4+Cd44+/+CD45.1 and GFP/FOXP3–CD4+Cd44–/–CD45.2 T cells into Rag–/– hosts. After 4 days, the numbers of induced CD3+GFP/FOXP3+ Tregs in the spleens of recipient animals were assessed and the ratio of Cd44–/– Tregs versus Cd44+/+ Tregs was determined (n = 3 Rag–/– recipient animals). Data represent mean ± SEM; *P < 0.05 vs. respective control by unpaired t test.