Hyaluronan synthesis inhibition impairs antigen presentation and delays transplantation rejection

Marshall, Payton L.; Nagy, Nadine; Kaber, Gernot; Barlow, Graham L.; Ramesh, Amrit; Xie, Bryan J.; Linde, Miles H.; Haddock, Naomi L.; Lester, Colin A.; Tran, Quynh-Lam; Vries, Christiaan R. de; Hargil, Aviv; Malkovskiy, Andrey V.; Gurevich, Irina; Martinez, Hunter A.; Kuipers, Hedwich F.; Yadava, Koshika; Zhang, Xiangyue; Evanko, Stephen P.; Gebe, John A.; Wang, Xi; Vernon, Robert B.; Motte, Carol de la; Wight, Thomas N.; Engleman, Edgar G.; Krams, Sheri M.; Meyer, Everett; Bollyky, Paul L.

doi:10.1016/j.matbio.2020.12.001

Cited by 9 publications

(4 citation statements)

References 83 publications

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“…In the lung, 4-MU reduces HA and ameliorates disease in mouse models of lung infection [ 85 , 200 , 201 ], lung metastases [202] , pulmonary hypertension [71] , and pulmonary fibrosis [203] . Work from our lab and others has shown that the immunosuppressive effect of 4-MU is mediated in large part through inhibition of antigen presentation and the induction of anti-inflammatory Foxp3+ Tregs [204] , [205] , [206] .…”

Section: Ha Is a Novel Therapeutic Target In Covid-19mentioning

confidence: 89%

Hyaluronan in the pathogenesis of acute and post-acute COVID-19 infection

et al. 2023

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Section: Ha Is a Novel Therapeutic Target In Covid-19mentioning

confidence: 89%

Hyaluronan in the pathogenesis of acute and post-acute COVID-19 infection

et al. 2023

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“…4-MU treatment resulted decreased islet CD44 (Figure 4A, 4B), suggesting that increased levels of islet CD44 may be driven by HA accumulation. Pericellular HA is known to stabilize CD44 on the cell surface in other systems 38 and that may also be relevant here.…”

Section: -Mu Treatment Is Effective In Mice With Established Diabetesmentioning

confidence: 89%

Inhibition of hyaluronan synthesis prevents β-cell loss in obesity-associated type 2 diabetes

Nagy

Kaber

Sunkari

et al. 2023

Preprint

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Pancreatic β-cell dysfunction and death are central to the pathogenesis of type 2 diabetes (T2D). We have identified a novel role for the inflammatory extracellular matrix polymer hyaluronan (HA) in this pathophysiology. Low levels of HA are present in healthy pancreatic islets. However, HA substantially accumulates in cadaveric islets of human T2D and islets of the db/db mouse model of T2D in response to hyperglycemia. Treatment with 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, or the deletion of the major HA receptor CD44, preserve glycemic control and insulin levels in db/db mice despite ongoing weight gain, indicating a critical role for this pathway in T2D pathogenesis. 4-MU treatment and the deletion of CD44 likewise preserve glycemic control in other settings of β-cell injury including streptozotocin treatment and islet transplantation. Mechanistically, we find that 4-MU increases the expression of the apoptosis inhibitor survivin, a downstream transcriptional target of CD44 dependent on HA/CD44 signaling, on β-cells such that caspase 3 activation does not result in β-cell apoptosis. These data indicate a role for HA accumulation in diabetes pathogenesis and suggest that it may be a viable target to ameliorate β-cell loss in T2D. These data are particularly exciting, because 4-MU is already an approved drug (also known as hymecromone), which could accelerate translation of these findings to clinical studies.

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“…T cells, which are the most abundant migrating leucocytes in afferent lymph, express transcripts for HA synthases, and can both synthesise and secrete HA [108]. Furthermore, synthesis via HAS 1 and HAS 2 was recently shown to be essential for stabilising T cell • DC adhesion and immune synapse formation, as well as the priming and Th1 polarisation of peptide-specific T cell responses in mice [111,112,170]. Although the HA mediating these effects appeared to derive from DCs rather than T cells, more recent studies have revealed that HA synthesised by T cells also plays an important contributory role [171].…”

Section: Significance Of the Ha Glycocalyx In Different Immune Cell Populations: Macrophages T Cells And Neutrophilsmentioning

confidence: 99%

Hyaluronan and Its Receptors: Key Mediators of Immune Cell Entry and Trafficking in the Lymphatic System

Johnson

Jackson

2021

Cells

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Entry to the afferent lymphatics marks the first committed step for immune cell migration from tissues to draining lymph nodes both for the generation of immune responses and for timely resolution of tissue inflammation. This critical process occurs primarily at specialised discontinuous junctions in initial lymphatic capillaries, directed by chemokines released from lymphatic endothelium and orchestrated by adhesion between lymphatic receptors and their immune cell ligands. Prominent amongst the latter is the large glycosaminoglycan hyaluronan (HA) that can form a bulky glycocalyx on the surface of certain tissue-migrating leucocytes and whose engagement with its key lymphatic receptor LYVE-1 mediates docking and entry of dendritic cells to afferent lymphatics. Here we outline the latest insights into the molecular mechanisms by which the HA glycocalyx together with LYVE-1 and the related leucocyte receptor CD44 co-operate in immune cell entry, and how the process is facilitated by the unusual character of LYVE-1 • HA-binding interactions. In addition, we describe how pro-inflammatory breakdown products of HA may also contribute to lymphatic entry by transducing signals through LYVE-1 for lymphangiogenesis and increased junctional permeability. Lastly, we outline some future perspectives and highlight the LYVE-1 • HA axis as a potential target for immunotherapy.

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Hyaluronan synthesis inhibition impairs antigen presentation and delays transplantation rejection

Cited by 9 publications

References 83 publications

Hyaluronan in the pathogenesis of acute and post-acute COVID-19 infection

Hyaluronan in the pathogenesis of acute and post-acute COVID-19 infection

Inhibition of hyaluronan synthesis prevents β-cell loss in obesity-associated type 2 diabetes

Hyaluronan and Its Receptors: Key Mediators of Immune Cell Entry and Trafficking in the Lymphatic System

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