Inhibition of Hyaluronan Synthesis Protects against Central Nervous System (CNS) Autoimmunity and Increases CXCL12 Expression in the Inflamed CNS

Abstract

Background: Hyaluronan accumulates in chronic demyelinated multiple sclerosis (MS) lesions. Results: 4-Methylumbelliferone (4MU) inhibits HA synthesis, is protective in active and passive MS models, modulates T-cell responses, and prevents CXCL12 suppression within inflamed and non-inflamed CNS tissue. Conclusion: Inhibition of hyaluronan synthesis protects against CNS inflammation. Significance: Study data substantiate a link between hyaluronan and CNS inflammation.

Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization

“…This is consistent with our recent report of 4-MU-mediated enhancement of Treg in mouse models of autoimmune diabetes (27) and with past work on the impact of 4-MU on EAE (22). Our data indicate that 4-MU also promotes increased expression of GITR, a key effector molecule for Treg (23,24).…”

“…In the present study, we have examined the impact of 4-MU, an inhibitor of HA synthesis, on disease progression in the murine EAE model of MS. We demonstrate that 4-MU can both prevent EAE and ameliorate established disease, corroborating earlier findings (22). Moreover, we show that 4-MU treatment alters the phenotypic polarization of T cells and their trafficking to inflamed CNS tissue that underlies disease progression in this model.…”

“…However, more recent findings suggest that, depending on the context, (aberrant) astrogliosis could play a pathological role in a variety of neurological diseases, including MS (41,42). It has been shown that astrogliosis is a major component contributing to HA deposition in EAE lesions (14,22). Reactive astrocytes produce high levels of HA, and this HA might in turn provide a feed-forward loop by signaling through CD44 on reactive astrocytes, thereby sustaining astrogliosis (43,44).…”

“…In addition, it has been shown that 4-MU treatment lowers HAS expression, thus reducing the production of HA (21). A recent report has demonstrated that 4-MU decreases the incidence of autoimmunity in EAE (22). However, the impact of 4-MU on astrogliosis, and lymphocyte polarization and trafficking has not been fully delineated.…”

Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis

“…One study reported that 4-MU treatment reduced MMP expression in a mouse model of collagen-induced arthritis (42). Another recent report suggested that 4-MU increased spinal cord expression of CXCL12 and decreased Th1 responses, while increasing numbers of Tregs (43). Here, we established that HA inhibits FOXP3 expression via a CD44-and ERK1/2-dependent pathway, that 4-MU promotes Treg numbers via increased differentiation, and that these Tregs constrained effector T cells at the site of autoimmunity.…”