Endotoxin free hyaluronan and hyaluronan fragments do not stimulate TNF-α, interleukin-12 or upregulate co-stimulatory molecules in dendritic cells or macrophages

Dong, Yifei; Arif, Arif; Olsson, Mia; Cali, Valbona; Hardman, Blair K; Dosanjh, Manisha; Lauer, Mark E.; Midura, Ronald J.; Hascall, Vincent C.; Brown, Kelly L.; Johnson, Pauline

doi:10.1038/srep36928

Cited by 65 publications

(68 citation statements)

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“…Although several reports describe the inflammatory activation of macrophages and dendritic cells by L‐HA we found no pro‐inflammatory activity of L‐HA paralleling recent findings of others . It has been suggested that the source of HA and endotoxin levels might explain the divergent data on the pro‐inflammatory effects of purified HA fragments . Our study using bacterial‐derived endotoxin‐free HA derivatives may support this notion.…”

Section: Resultsmentioning

confidence: 99%

Sulfated hyaluronan attenuates inflammatory signaling pathways in macrophages involving induction of antioxidants

et al. 2017

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It is well recognized that high molecular weight hyaluronan (H-HA) exerts potent anti-inflammatory effects while its fragmentation into low molecular weight HA (L-HA) is discussed to promote inflammation. Chemical modification of HA with sulfate groups has been shown to foster its anti-inflammatory activity which seems to be maintained in sulfated low molecular weight HA derivatives (sL-HA). However, the molecular mechanisms by which sL-HA produces its anti-inflammatory activity are not understood. In this study, we used global quantitative proteomics combined with targeted analysis of key proteins to characterize the effect of sL-HA on fully differentiated human inflammatory macrophages (iMФ). Culture of iMФ with sL-HA did not affect cell viability but resulted in a reduced pro-inflammatory cytokine response of iMФ after activation indicating a profound counter-regulation of their initial inflammatory phenotype. Rapid internalization of sL-HA involving CD44 and scavenger receptors was observed. Furthermore, an upregulation of the antioxidants SOD2 and SOD3 was found while no oxidative stress was induced. Consequently, activity of transcription factors for inflammatory gene expression was downregulated in iMФ with sL-HA after activation whereas anti-inflammatory proteins were induced. This study proves anti-inflammatory properties of sL-HA and provides information on its regulatory mode of action on iMФ. This article is protected by copyright. All rights reserved.

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Section: Resultsmentioning

confidence: 99%

Sulfated hyaluronan attenuates inflammatory signaling pathways in macrophages involving induction of antioxidants

et al. 2017

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“…4,6 The induction of constitutive HA binding by the alveolar environment is a striking feature, as monocytes and PM^do not normally bind detectable levels of exogenously added HA, unless they are exposed to inflammatory stimuli. 24,27,28 However, AM^are not unique in their constitutive ability to engage HA, as splenic F4/80 þ macrophages can also bind HA, 29 and PM^are recruited to the site of liver injury in a CD44-and HA-dependent manner. 30 Together, these highlight the importance of environmental imprinting on HA binding and macrophage phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…L-cell conditioned media containing CSF-1 were generated from L929 fibroblast cells and tissue culture supernatant from J558L cells was the source of CSF-2, as described previously. 16,29 Fluoresceinconjugated HA was prepared using hyaluronic acid sodium salt from Rooster comb (Sigma-Aldrich, St. Louis, MO), as described previously. 43 High-molecular-weight HA (Lifecore Biomedical, Chaska, MN) was conjugated with Alexa Fluor-647 by AbLab (UBC) for HA-A647.…”

Section: Methodsmentioning

confidence: 99%

“…BM was isolated from murine femurs and tibia, and CSF-1-derived BMDMs were generated as previously described. 29 Macrophage stimulation with CSF-2 and ROZ. CSF-1 BMDMs (2 Â 10 5 ) were collected on day 5 and cultured in 200 ml Dulbecco's modified Eagle's medium DMEM (Invitrogen, Carlsbad, CA) with 10% fetal calf serum in nontissue culture-treated 96-well plates in the presence or absence of 4% CSF-2 containing supernatant for 48 h. Cells were then analyzed by FC.…”

Section: Induction Of Lung Inflammation and Adoptive Monocyte Transfermentioning

confidence: 99%

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The survival of fetal and bone marrow monocyte-derived alveolar macrophages is promoted by CD44 and its interaction with hyaluronan

et al. 2018

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Alveolar macrophages maintain lung homeostasis by performing important roles in immunosurveillance and lung surfactant catabolism. They express high levels of CD44 and are one of the few macrophage populations that constitutively bind hyaluronan, a ligand for CD44 and component of pericellular and extracellular matrices. Using adoptive transfer experiments and a mouse model of inflammation, we found that alveolar macrophages are initially depleted after an inflammatory insult then rapidly self-renew and return to original numbers after the resolution phase. Monocytes recruited to an inflamed lung differentiate and contribute to the alveolar macrophage pool, but this occurs over a much slower time frame than alveolar macrophage self-renewal. CD44 expression on both fetal and bone marrow-derived alveolar macrophages promoted their survival and provided a competitive advantage over CD44-deficient alveolar macrophages at homeostasis and after inflammation. CD44-mediated hyaluronan binding was induced by the alveolar environment, and this interaction promoted alveolar macrophage survival both ex vivo and in vivo. Without CD44, alveolar macrophages lacked a hyaluronan coat, were more susceptible to death, and were present at lower numbers in the alveolar space. This demonstrates a new role for CD44 and hyaluronan in promoting alveolar macrophage survival.

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“…Although, IκK/NF-κB signaling is the main proinflammatory pathway associated with TLR activation, it does not regulate developmental myelination or remyelination (10). Despite evidence that HAf may mediate adult myelination failure by utilizing a proinflammatory signaling pathway (6), the proinflammatory actions of HAf have been recently questioned and attributed to bacterial endotoxin contamination (11). Consequently, the mechanistic roles for MDa HA and/or HAf in regulating OPC differentiation in chronic WMI remain poorly defined.…”

Section: Introductionmentioning

confidence: 99%

A TLR/AKT/FoxO3 immune tolerance–like pathway disrupts the repair capacity of oligodendrocyte progenitors

Srivastava¹,

Diba²,

Dean³

et al. 2018

Journal of Clinical Investigation

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ers by interactions of FoxO3 with the chromatin-remodeling factor Brg1 and the TF Olig2, which are involved in control of OPC differentiation (14-16). Hence, central myelination failure is regulated by a noncanonical TLR4/AKT/FoxO3 signaling pathway utilized by bHAf to induce a tolerance-like state that selectively constrains OPC maturation and myelination. ResultsNeonatal hypoxic-ischemic WMI promotes MDa HA depolymerization. To investigate the status of MDa HA in chronic neonatal WMI, we employed our preterm-equivalent rat hypoxia-ischemia (H-I) model, which generates myelination failure and replicates key features of human WMI ( Figure 1A) (17). MDa HA turnover in the ECM after H-I was visualized with a biotinylated HA-binding protein (HABP) and costained with glial fibrillary acidic protein (GFAP) as a marker of WMI. Unlike in age-matched uninpro-myelination signal (13). This tolerance-like action of bHAf was mediated through TLR4 but not via CD44 or TLR2. As in TLR4-mediated IT, bHAf 's influence on myelination was reversible when MDa HA depolymerization was attenuated or bHAf was removed. AKT desensitization was similarly reversible in vivo in neonatal WMI. Moreover, bHAf actions were mediated via a noncanonical TRIF-dependent pathway, also involved in IT, rather than the canonical MyD88 arm of TLR4 signaling. AKT desensitization resulted in maturation-dependent activation of the FoxO3 transcription factor (TF), which selectively constrained preOL maturation in a bHAf-dependent fashion. A role for activated FoxO3 in human myelination failure was supported by selective localization of nuclear FoxO3 to OPCs in human preterm WMI and multiple sclerosis (MS) plaques. bHAf-mediated OPC maturation arrest appears to be regulated at the FoxO3 and myelin basic protein (MBP) promot- (Contralateral). Only the lesion group had a significant reduction in HA recovery. (E) Incubation of MDa HA with the lesion lysate generated HAf below ~650 kDa. Lesion-lysate activity was sensitive to heat inactivation but insensitive to deferoxamine (50 μM). B and C: control n = 2; H-I n = 4 animals for each age group (P4 and P14). D: n = 6 (H-I), n = 5 (control), and n = 4 (hypoxia) animals (P7). E: n = 4 separate experiments on 4 different animals at P4 after H-I at P3; one representative experiment is shown. *P < 0.05 by ANOVA. Mean ± SD. Scale bars: 300 μm (B and C). The Journal of Clinical Investigation R E S E A R C H A R T I C L E2 0 2 7 jci.orgVolume 128 Number 5 May 2018 with MBP-labeled oligodendrocytes (Supplemental Figure 2A). To confirm de novo progressive myelin generation, we undertook ultrastructural studies that identified axons wrapped with multilamellar myelin sheaths ( Figure 2B). In contrast to vehicle-treated slices, which displayed robust myelination of the corpus callosum, slices incubated with MDa HA until 21 days in vitro (DIV21) displayed a pronounced reduction in myelinated axons ( Figure 2C). Myelination failure was not related to decreased OPC survival, since MDa HA treatment did not enhance OPC degeneratio...

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Endotoxin free hyaluronan and hyaluronan fragments do not stimulate TNF-α, interleukin-12 or upregulate co-stimulatory molecules in dendritic cells or macrophages

Cited by 65 publications

References 54 publications

Sulfated hyaluronan attenuates inflammatory signaling pathways in macrophages involving induction of antioxidants

Sulfated hyaluronan attenuates inflammatory signaling pathways in macrophages involving induction of antioxidants

The survival of fetal and bone marrow monocyte-derived alveolar macrophages is promoted by CD44 and its interaction with hyaluronan

A TLR/AKT/FoxO3 immune tolerance–like pathway disrupts the repair capacity of oligodendrocyte progenitors

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