Modified High-Molecular-Weight Hyaluronan Promotes Allergen-Specific Immune Tolerance

Gebe, John A.; Yadava, Koshika; Ruppert, Shannon M.; Marshall, Payton L.; Hill, Paul B.; Falk, Ben; Sweere, Johanna M.; Han, Hongwei; Kaber, Gernot; Harten, Ingrid A.; Medina, Carlos O.; Mikecz, Katalin; Ziegler, Steven F.; Balaji, Swathi; Keswani, Sundeep G.; Perez, Vinicio A. de Jesus; Butte, Manish J.; Nadeau, Kari; Altemeier, William A.; Fanger, Neil A.; Bollyky, Paul L.

doi:10.1165/rcmb.2016-0111oc

Cited by 29 publications

(31 citation statements)

References 54 publications

(60 reference statements)

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“…Cells were counted and used for assays as described. 19 For immunophenotyping, cells were lifted with cold PBS and processed according to our previously published flow cytometry protocol. 20 All immune cells from spleens, lymph nodes and wounds were stained with Zombie Aqua Viability Dye, B220, I-A/I-E, CD11c, CD11b + , F4/80, CD49b, Gr-1, CD3 and CD8 according to the flow cytometry protocol.…”

Section: Chemicals Antibiotics and Reagentsmentioning

confidence: 99%

The Immune Response to Chronic Pseudomonas aeruginosa Wound Infection in Immunocompetent Mice

Sweere

Ishak

Sunkari

et al. 2020

Advances in Wound Care

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Objective: Our goal was to develop a chronic wound model in mice that avoids implantation of foreign material or impaired immunity and to use this to characterize the local and systemic immune response associated with Pseudomonas aeruginosa infection. Approach: We generated bilateral full-thickness dermal wounds in healthy 10-12-week-old C57Bl6 mice. We waited 24 h to inoculate the developing wound eschar at these sites. We performed careful titration experiments with luminescent strains of P. aeruginosa to identify bacterial inoculation concentrations that consistently established stable infections in these animals. We performed flow cytometry-based immunophenotyping of immune cell infiltrates at the wound site, spleen, and draining lymph nodes over time. Finally, we compared inflammatory responses seen in wound inoculation with planktonic bacteria, preformed biofilm, and heat-killed (HK) P. aeruginosa. Results: Using this delayed inoculation model and 7.5-2.5 • 10 2 CFU/mL of PAO1 we consistently established stable infections that lasted at 10 days in duration. During early infection, we detected a strong upregulation of inflammatory cytokines and neutrophil infiltration at the wound site, while natural killer (NK) cells and dendritic cells (DCs) were reduced. At the systemic level, only plasmacytoid DCs were increased early in infection. During later stages, there was systemic upregulation of B cells, T cells, and macrophages, whereas NK cells and interferon killer DCs were reduced. Infections with P. aeruginosa biofilms were not more virulent than infections with planktonic P. aeruginosa, whereas treatment with HK P. aeruginosa only induces a short-term inflammatory state. Innovation: We describe a versatile wound model of chronic P. aeruginosa infection that lasts 10 days without causing sepsis or other excessive morbidity. Conclusion: This model may facilitate the study of chronic wound infections in immunocompetent mice. Our findings also highlight the induction of early innate immune cell populations during P. aeruginosa infection.

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Section: Chemicals Antibiotics and Reagentsmentioning

confidence: 99%

The Immune Response to Chronic Pseudomonas aeruginosa Wound Infection in Immunocompetent Mice

Sweere

Ishak

Sunkari

et al. 2020

Advances in Wound Care

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“…OTII and DO11.10 mice were purchased from The Jackson Laboratory (Bar Harbor, Me). OTII mice were crossed to supplemented with 10% Fetal Bovine Serum (Hyclone, Logan, Utah), 100 μg/ml Penicillin, 100 U/ml Streptomycin, and 1 mM sodium pyruvate (Invitrogen, Carlsbad, CA) as previously described (64). Human monocyte-derived DC were generated as previously described (65).…”

Section: Mouse Handlingmentioning

confidence: 99%

“…Isolation and culture of mouse leukocyte populations: Total leukocytes were isolated from LN and spleen from 8 to 12 week old mice as previously described (64). CD4+ T-cells were isolated from the pooled cell suspensions using an EasySep™ Mouse CD4+ T Cell Isolation Kit from Stemcell Technologies (Vancouver, Canada) following the manufacturer's instructions.…”

Section: Mouse Handlingmentioning

confidence: 99%

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Hyaluronan Synthesis Inhibition Impairs Antigen Presentation and Delays Transplantation Rejection

Marshall

Nagy

Kaber

et al. 2020

Preprint

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A coat of pericellular hyaluronan surrounds mature dendritic cells (DC) and contributes to cell-cell interactions. We asked whether 4-methylumbelliferone (4MU), an oral inhibitor of HA synthesis, could inhibit antigen presentation. We find that 4MU treatment reduces pericellular hyaluronan, destabilizes interactions between DC and T-cells, and prevents T-cell proliferation in vitro and in vivo. These effects were observed only when 4MU was added prior to initial antigen presentation but not later, consistent with 4MU-mediated inhibition of de novo antigenic responses. Building on these findings, we find that 4MU delays rejection of allogeneic pancreatic islet transplant and allogeneic cardiac transplants in mice and suppresses allogeneic T-cell activation in human mixed lymphocyte reactions. We conclude that 4MU, an approved drug, may have benefit as an adjunctive agent to delay transplantation rejection.

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“…An alternative explanation is that smaller sized HA fragments displace HMW-HA bound to CD44, and disrupt its protective, immunosuppressive effect ( 76 ). In some cells, HMW-HA inhibits NF-κb signaling ( 77 ), and so its displacement by HA fragments would result in a proinflammatory NF-κb response. Another explanation for the variation in results seen with different sized HA fragments may arise from the use of polydisperse HA where a range of HA sizes within a single preparation compete for receptors to initiate the inflammatory signal ( 78 ).…”

Section: Ha In the Inflamed Lungmentioning

confidence: 99%

Hyaluronan and Its Interactions With Immune Cells in the Healthy and Inflamed Lung

et al. 2018

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Hyaluronan is a hygroscopic glycosaminoglycan that contributes to both extracellular and pericellular matrices. While the production of hyaluronan is essential for mammalian development, less is known about its interaction and function with immune cells. Here we review what is known about hyaluronan in the lung and how it impacts immune cells, both at homeostasis and during lung inflammation and fibrosis. In the healthy lung, alveolar macrophages provide the first line of defense and play important roles in immunosurveillance and lipid surfactant homeostasis. Alveolar macrophages are surrounded by a coat of hyaluronan that is bound by CD44, a major hyaluronan receptor on immune cells, and this interaction contributes to their survival and the maintenance of normal alveolar macrophage numbers. Alveolar macrophages are conditioned by the alveolar environment to be immunosuppressive, and can phagocytose particulates without alerting an immune response. However, during acute lung infection or injury, an inflammatory immune response is triggered. Hyaluronan levels in the lung are rapidly increased and peak with maximum leukocyte infiltration, suggesting a role for hyaluronan in facilitating leukocyte access to the injury site. Hyaluronan can also be bound by hyaladherins (hyaluronan binding proteins), which create a provisional matrix to facilitate tissue repair. During the subsequent remodeling process hyaluronan concentrations decline and levels return to baseline as homeostasis is restored. In chronic lung diseases, the inflammatory and/or repair phases persist, leading to sustained high levels of hyaluronan, accumulation of associated immune cells and an inability to resolve the inflammatory response.

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Modified High-Molecular-Weight Hyaluronan Promotes Allergen-Specific Immune Tolerance

Cited by 29 publications

References 54 publications

The Immune Response to Chronic Pseudomonas aeruginosa Wound Infection in Immunocompetent Mice

The Immune Response to Chronic Pseudomonas aeruginosa Wound Infection in Immunocompetent Mice

Hyaluronan Synthesis Inhibition Impairs Antigen Presentation and Delays Transplantation Rejection

Hyaluronan and Its Interactions With Immune Cells in the Healthy and Inflamed Lung

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