Hyaluronan Anchored to Activated CD44 on Central Nervous System Vascular Endothelial Cells Promotes Lymphocyte Extravasation in Experimental Autoimmune Encephalomyelitis

Winkler, Clayton W.; Foster, Scott; Matsumoto, Steven G.; Preston, Marnie; Xing, Rubing; Bebo, Bruce F.; Banine, Fatima; Berny‐Lang, Michelle A.; Itakura, Asako; McCarty, Owen J. T.; Sherman, Larry S.

doi:10.1074/jbc.m112.356287

Cited by 46 publications

(59 citation statements)

References 57 publications

(73 reference statements)

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“…There are also indications that CD44 contributes to lymphocyte adhesion and diapedesis through the blood-brain barrier (30,31) as well as specific trafficking to inflamed sites (32). Although reports on the implications of CD44 deficiency for neuroinflammation in EAE are conflicting (18,26,33), it has been shown that blocking CD44 using a monoclonal antibody prevents EAE by reducing T-cell infiltration into the CNS (31).…”

Section: Discussionmentioning

confidence: 99%

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

Kuipers

Rieck

Gurevich

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The extracellular matrix polysaccharide hyaluronan (HA) accumulates at sites of autoimmune inflammation, including white matter lesions in multiple sclerosis (MS), but its functional importance in pathogenesis is unclear. We have evaluated the impact of 4-methylumbelliferone (4-MU), an oral inhibitor of HA synthesis, on disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Treatment with 4-MU decreases the incidence of EAE, delays its onset, and reduces the severity of established disease. 4-MU inhibits the activation of autoreactive T cells and prevents their polarization toward a Th1 phenotype. Instead, 4-MU promotes polarization toward a Th2 phenotpye and induction of Foxp3+ regulatory T cells. Further, 4-MU hastens trafficking of T cells through secondary lymphoid organs, impairs the infiltration of T cells into the CNS parenchyma, and limits astrogliosis. Together, these data suggest that HA synthesis is necessary for disease progression in EAE and that treatment with 4-MU may be a potential therapeutic strategy in CNS autoimmunity. Considering that 4-MU is already a therapeutic, called hymecromone, that is approved to treat biliary spasm in humans, we propose that it could be repurposed to treat MS.

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Section: Discussionmentioning

confidence: 99%

“…Upon injury, however, reactive astrocytes are the main producers of abundant amounts of HA, which accumulate in the damaged areas (14,16,17). As such, HA is highly abundant within demyelinated lesions in MS and in EAE, where it has been implicated in the extravasation of activated T cells into the CNS (14,18).…”

mentioning

confidence: 99%

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

Kuipers

Rieck

Gurevich

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Disruption of the HA synthase 3 gene led to minor leukocyte infiltrate in the dextran sulfate sodium-induced experimental colitis model (90). Injection of hyaluronidase transiently ameliorated the symptoms and delayed the onset of experimental autoimmune encephalomyelitis due to degradation of HA and impaired CD4 + T-cell extravasation, while administration of an inhibitor of HA synthesis to DORmO mice prevented development of invasive insulitis and hyperglycemia (21,24).…”

Section: The Role Of Ha In Type 1 Diabetes Pathogenesis Ha a Regulatmentioning

confidence: 99%

Thinking Outside the Cell: A Key Role for Hyaluronan in the Pathogenesis of Human Type 1 Diabetes

Bogdani

2016

Diabetes

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“…Primary BCEC microvessels were obtained from LACV and mock-infected mice at 3 dpi according to a previously published protocol [49] with the exception that the OB and tract were processed separately from cortices. Isolation of microvessels was confirmed by microscopic analysis.…”

Section: Bcec Isolation 2d-dige Protein Expression Profiling and Masmentioning

confidence: 99%

Capillaries in the olfactory bulb but not the cortex are highly susceptible to virus-induced vascular leak and promote viral neuroinvasion

et al. 2015

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Viral neuroinvasion is a critical step in the pathogenesis of viral encephalitis. Multiple mechanisms of neuroinvasion have been identified, but their relative contribution to central nervous system (CNS) infection remains unclear for many viruses. In this study, we examined neuroinvasion of the mosquito-borne bunyavirus La Crosse (LACV), the leading cause of pediatric viral encephalitis in the USA. We found that the olfactory bulb (OB) and tract were the initial areas of CNS virus infection in mice. Removal of the OB reduced the incidence of LACV-induced disease demonstrating the importance of this area to neuroinvasion. However, we determined that infection of the OB was not due to axonal transport of virus from olfactory sensory neurons as ablation of these cells did not affect viral pathogenesis. Instead, we found that OB capillaries were compromised allowing leakage of virus-sized particles into the brain. Analysis of OB capillaries demonstrated specific alterations in cytoskeletal and Rho GTPase protein expression not observed in capillaries from other brain areas such as the cortex where leakage did not occur. Collectively, these findings indicate that LACV neuroinvasion occurs through hematogenous spread in specific brain regions where capillaries are prone to virus-induced activation such as the OB. Capillaries in these areas may be "hot spots" that are more susceptible to neuroinvasion not only for LACV, but other neurovirulent viruses as well.

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Hyaluronan Anchored to Activated CD44 on Central Nervous System Vascular Endothelial Cells Promotes Lymphocyte Extravasation in Experimental Autoimmune Encephalomyelitis

Cited by 46 publications

References 57 publications

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

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

Thinking Outside the Cell: A Key Role for Hyaluronan in the Pathogenesis of Human Type 1 Diabetes

Capillaries in the olfactory bulb but not the cortex are highly susceptible to virus-induced vascular leak and promote viral neuroinvasion

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