Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis
Nadine Nagy, … , Thomas N. Wight, Paul L. Bollyky
Nadine Nagy, … , Thomas N. Wight, Paul L. Bollyky
Published October 1, 2015; First published September 14, 2015
Citation Information: J Clin Invest. 2015;125(10):3928-3940. https://doi.org/10.1172/JCI79271.
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Categories: 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 9

4-MU treatment promotes FOXP3 induction.

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4-MU treatment promotes FOXP3 induction. (A) FOXP3 levels following indu...
(A) FOXP3 levels following induction from CD4+GFP/FOXP3– T cell precursors performed in the setting of anti-CD3, with or without anti-CD28 and/or anti-CD44 antibody costimulation. (B) Pooled data for 4 independent experimental replicates for the representative data in A. (C) Fold change in pERK1/2 MFI over time following CD44 crosslinking. The data shown incorporate 3 experimental replicates. (D) CD25 and GFP/FOXP3 levels following activation of CD4+GFP/FOXP3– T cells in the setting of TGF-β and IL-2, with or without CD44 costimulation and/or the ERK1/2 inhibitor SUO126. (E) Pooled data for 6 independent experimental replicates for the representative data in D. (F–K) CD44 staining of representative pancreatic tissue sections from BALB/c (control) or DORmO mice fed either 4-MU or control chow. (L) Average CD44+ area of islets for these mice. At least 25 islets were visualized per mouse (n = 6). Original magnification, ×40. Data represent mean ± SEM; *P < 0.05 vs. respective control and control for each time point by unpaired t test.