Inhibition of Fucosylation Reshapes Inflammatory Macrophages and Suppresses Type II Collagen–Induced Arthritis

Li, Jun; Hsu, Hui‐Chen; Ding, Yubin; Li, Hao; Wu, Qi; Yang, PingAr; Luo, Bao; Rowse, Amber L.; Spalding, David M.; Bridges, S. Louis; Mountz, John D.

doi:10.1002/art.38711

Cited by 72 publications

(88 citation statements)

References 44 publications

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“…Induction of agalactosylated glycan in total IgG glycome was previously associated with HIV infection and inflammation and was confirmed in our study . In addition, we revealed that certain glycomic alterations that have been associated with inflammation (a loss of disialylated glycans and an increase of fucosylated glycans) and reduction of ADCC activity (an increase of fucosylated glycans), persist during suppressed HIV infection . These glycomic dysregulations may underlie chronic inflammation and immunological dysfunction during suppressed HIV infection thus contributing to the pathogenesis of HIV‐associated comorbidities.…”

Section: Discussionsupporting

confidence: 87%

“…These results confirm some previously reported data and report new IgG glycomic alterations that associate with HIV infection and persist despite suppressive ART. In particular, decreased levels of IgG sialylated glycans, which is associated with proinflammatory activity, and increased levels of IgG fucosylated glycans, which is associated with lower ADCC and higher inflammation, regardless of the ART‐suppression status.…”

Section: Resultsmentioning

confidence: 99%

“…Certain IgG glycan traits were combined into categories, glycan structures that contain galactose (G0 = agalactosylated, G1 = mono-galactosylated, G2 = digalactosylated) or that contain sialic acid (S = sialylated), fucose (F = fucosylated), or a bisecting GlcNAc (B = bisected) (Supplemental Table 2). Levels of disialy- [38][39][40] and increased levels of IgG fucosylated glycans, which is associated with lower ADCC and higher inflammation, [35][36][37]58,59 regardless of the ART-suppression status.…”

Section: Hiv Infection Is Associated With Persistent Alterations In Tmentioning

confidence: 99%

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Frontline Science: Plasma and immunoglobulin G galactosylation associate with HIV persistence during antiretroviral therapy

Vadrevu

Trbojević‐Akmačić

Kossenkov

et al. 2018

Journal of Leukocyte Biology

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Global antibody glycosylation is dynamic and plays critical roles in shaping different immunological outcomes and direct antibody functionality during HIV infection. However, the relevance of global antibody or plasma glycosylation patterns to HIV persistence after antiretroviral therapy (ART) has not been characterized. First, we compared glycomes of total plasma and isolated immunoglobulin G (IgG) from HIV+ ART-suppressed, HIV+ viremic, and HIV-negative individuals. Second, in ART-suppressed individuals, we examined the associations between glycomes and (1) levels of cell-associated HIV DNA and RNA in PBMCs and isolated CD4+ T cells, (2) CD4 count and CD4%, and (3) expression of CD4+ T-cell activation markers. HIV infection is associated with persistent alterations in the IgG glycome including decreased levels of disialylated glycans, which is associated with a lower anti-inflammatory activity, and increased levels of fucosylated glycans, which is associated with lower antibody-dependent cell-mediated cytotoxicity (ADCC). We also show that levels of certain mono- and digalactosylated nonfucosylated glycomic traits (A2G1, A2G2, and A2BG2), which have been reported to be associated with higher ADCC and higher anti-inflammatory activities, exhibit significant negative correlations with levels of cell-associated total HIV DNA and HIV RNA in ART-suppressed individuals. Finally, levels of certain circulating anti-inflammatory glycans are associated with higher levels of CD4 T cells and lower levels of T-cell activation. Our findings represent the first proof-of-concept evidence that glycomic alterations, known to be associated with differential states of inflammation and ADCC activities, are also associated with levels of HIV persistence in the setting of ART suppression.

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Hiv Infection Is Associated With Persistent Alterations In Tmentioning

confidence: 99%

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Frontline Science: Plasma and immunoglobulin G galactosylation associate with HIV persistence during antiretroviral therapy

Vadrevu

Trbojević‐Akmačić

Kossenkov

et al. 2018

Journal of Leukocyte Biology

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“…The benefit of 2-F-Fuc against various diseases was shown in in vivo mouse models of cancer and sickle cell diseases (Belcher et al, 2015; Okeley et al, ). An indirect inhibitor, 2-deoxy-galactose, was also shown to be effective against arthritis (Li et al, 2014). These studies underscore the potential of fucosylation inhibitors as direct therapeutics.…”

Section: Discussionmentioning

confidence: 82%

An Alkynyl-Fucose Halts Hepatoma Cell Migration and Invasion by Inhibiting GDP-Fucose-Synthesizing Enzyme FX, TSTA3

Kizuka

Nakano

Yamaguchi

et al. 2017

Cell Chemical Biology

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Fucosylation is a glycan modification critically involved in cancer and inflammation. Although potent fucosylation inhibitors are useful for basic and clinical research, only a few inhibitors have been developed. Here, we focus on a fucose analog with an alkyne group, 6-alkynyl-fucose (6-Alk-Fuc), which is used widely as a detection probe for fucosylated glycans, but is also suggested for use as a fucosylation inhibitor. Our glycan analysis using lectin and mass spectrometry demonstrated that 6-Alk-Fuc is a potent and general inhibitor of cellular fucosylation, with much higher potency than the existing inhibitor, 2-fluoro-fucose (2-F-Fuc). The action mechanism was shown to deplete cellular GDP-Fuc, and the direct target of 6-Alk-Fuc is FX (encoded by TSTA3), the bifunctional GDP-Fuc synthase. We also show that 6-Alk-Fuc halts hepatoma invasion. These results highlight the unappreciated role of 6-Alk-Fuc as a fucosylation inhibitor and its potential use for basic and clinical science.

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“…7 Progression of OA occurs in conjunction with an increase in pro-inflammatory (M1) macrophages which not only exacerbate articular damage, but also reduce the chondrogenic potential of implanted MSCs. 4, 8 …”

Section: Introductionmentioning

confidence: 99%

The effect of local anesthetic on pro-inflammatory macrophage modulation by mesenchymal stromal cells

Gray

Marrero-Berríos

Weinberg

et al. 2016

International Immunopharmacology

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Administering local anesthetics (LAs) peri- and post-operatively aims to prevent or mitigate pain in surgical procedures and after tissue injury in cases of osteoarthritis (OA) and other degenerative diseases. Innovative tissue protective and reparative therapeutic interventions such as mesenchymal stromal cells (MSCs) are likely to be exposed to co-administered drugs such as LAs. Therefore, it is important to determine how this exposure affects the therapeutic functions of MSCs and other cells in their target microenvironment. In these studies, we measured the effect of LAs, lidocaine and bupivacaine, on macrophage viability and pro-inflammatory secretion. We also examined their effect on modulation of the macrophage pro-inflammatory phenotype in an in vitro co-culture system with MSCs, by quantifying macrophage tumor necrosis factor (TNF)-α secretion and MSC prostaglandin E2 (PGE2) production. Our studies indicate that both LAs directly attenuated macrophage TNF-α secretion, without significantly affecting viability, in a concentration- and potency-dependent manner. LA-mediated attenuation of macrophage TNF-α was sustained in co-culture with MSCs, but MSCs did not further enhance this anti-inflammatory effect. Concentration- and potency-dependent reductions in macrophage TNF-α were concurrent with decreased PGE2 levels in the co-cultures further indicating MSC-independent macrophage attenuation. MSC functional recovery from LA exposure was assessed by pre-treating MSCs with LAs prior to co-culture with macrophages. Both MSC attenuation of TNF-α and PGE2 secretion were impaired by pre-exposure to the more potent bupivacaine and high dose of lidocaine in a concentration-dependent manner. Therefore, LAs can affect anti-inflammatory function by both directly attenuating macrophage inflammation and MSC secretion and possibly by altering the local microenvironment which can secondarily reduce MSC function. Furthermore, the LA effect on MSC function may persist even after LA removal.

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Inhibition of Fucosylation Reshapes Inflammatory Macrophages and Suppresses Type II Collagen–Induced Arthritis

Cited by 72 publications

References 44 publications

Frontline Science: Plasma and immunoglobulin G galactosylation associate with HIV persistence during antiretroviral therapy

Frontline Science: Plasma and immunoglobulin G galactosylation associate with HIV persistence during antiretroviral therapy

An Alkynyl-Fucose Halts Hepatoma Cell Migration and Invasion by Inhibiting GDP-Fucose-Synthesizing Enzyme FX, TSTA3

The effect of local anesthetic on pro-inflammatory macrophage modulation by mesenchymal stromal cells

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