Inhibitors of Human Neuraminidase Enzymes Block Transmigration in vitro

Howlader, Md. Amran; Guo, Tianlin; Cairo, Christopher W.

doi:10.3389/fmolb.2022.835757

Cited by 4 publications

(3 citation statements)

References 46 publications

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“…In neutrophils, activation by fMLF leads to increased sialidase activity on the cell membrane, 77 and Clostridium perfringens neuraminidase removal of sialic acids from CD11b/CD18 exposes activation epitopes that enhances adhesion 78 . Sialidase inhibitors can prevent immune cell migration into inflammatory lesions 32,38,39,79–81 . Combined with the above observations, our results suggest that NEU3 removes cell‐surface sialic acids to prime neutrophils.…”

Section: Discussionsupporting

confidence: 64%

“…78 Sialidase inhibitors can prevent immune cell migration into inflammatory lesions. 32,38,39,[79][80][81] Combined with the above observations, our Adhesion of primed neutrophils to the endothelial lining is important to induce outside-in signaling, 82 allowing for the expression of adhesive markers on the surface of neutrophils. 55,83 CD66 are glycoproteins that play a role in neutrophils adhesion to E-selectin on local endothelial cells through the presentation of CD15s epitope.…”

Section: Discussionmentioning

confidence: 65%

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The extracellular sialidase NEU3 primes neutrophils

Kirolos

Pilling

2022

Journal of Leukocyte Biology

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Some extracellular glycoconjugates have sialic acid as the terminal sugar, and sialidases are enzymes that remove this sugar. Mammals have 4 sialidases and can be elevated in inflammation and fibrosis. In this report, we show that incubation of human neutrophils with the extracellular human sialidase NEU3, but not NEU1, NEU2 or NEU4, induces human male and female neutrophils to change from a round to a more amoeboid morphology, causes the primed human neutrophil markers CD11b, CD18, and CD66a to localize to the cell cortex, and decreases the localization of the unprimed human neutrophil markers CD43 and CD62-L at the cell cortex. NEU3, but not the other 3 sialidases, also causes human male and female neutrophils to increase their F-actin content. Human neutrophils treated with NEU3 show a decrease in cortical levels of Sambucus nigra lectin staining and an increase in cortical levels of peanut agglutinin staining, indicating a NEU3-induced desialylation. The inhibition of NEU3 by the NEU3 inhibitor 2-acetylpyridine attenuated the NEU3 effect on neutrophil morphology, indicating that the effect of NEU3 is dependent on its enzymatic activity. Together, these results indicate that NEU3 can prime human male and female neutrophils, and that NEU3 is a potential regulator of inflammation.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 65%

The extracellular sialidase NEU3 primes neutrophils

Kirolos

Pilling

2022

Journal of Leukocyte Biology

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“…Moreover, in the respective NEU-KO mouse models, NEU1 and NEU3 were identified as pro-inflammatory regulators of leukocyte recruitment upon LPS-stimulation with NEU1 regulating levels of pro-inflammatory cytokines whereas NEU4 exhibits an anti-inflammatory effect, negatively regulating monocyte, neutrophil and natural killer cell infiltration [ 81 ]. In human lymphocyte Jurkat T cells, NEU1, NEU3 and NEU4 were determined to be positive regulators of transmigration using cytokines as chemoattractants [ 82 ]. In line with this, NEU1 and NEU3 can be found in activated human T-lymphocytes, where they lead to an increased secretion of the pro-inflammatory cytokine IFN-γ and they are able to regulate LPS-induced cytokine production in leukocytes [ 83 , 84 , 85 ].…”

Section: Neuraminidases and Their Role In The Immune Systemmentioning

confidence: 99%

Neuraminidases—Key Players in the Inflammatory Response after Pathophysiological Cardiac Stress and Potential New Therapeutic Targets in Cardiac Disease

Heimerl

Gausepohl

Mueller

et al. 2022

Biology

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Glycoproteins and glycolipids on the cell surfaces of vertebrates and higher invertebrates contain α-keto acid sugars called sialic acids, terminally attached to their glycan structures. The actual level of sialylation, regulated through enzymatic removal of the latter ones by NEU enzymes, highly affects protein-protein, cell-matrix and cell-cell interactions. Thus, their regulatory features affect a large number of different cell types, including those of the immune system. Research regarding NEUs within heart and vessels provides new insights of their involvement in the development of cardiovascular pathologies and identifies mechanisms on how inhibiting NEU enzymes can have a beneficial effect on cardiac remodelling and on a number of different cardiac diseases including CMs and atherosclerosis. In this regard, a multitude of clinical studies demonstrated the potential of N-acetylneuraminic acid (Neu5Ac) to serve as a biomarker following cardiac diseases. Anti-influenza drugs i.e., zanamivir and oseltamivir are viral NEU inhibitors, thus, they block the enzymatic activity of NEUs. When considering the improvement in cardiac function in several different cardiac disease animal models, which results from NEU reduction, the inhibition of NEU enzymes provides a new potential therapeutic treatment strategy to treat cardiac inflammatory pathologies, and thus, administrate cardioprotection.

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Targeting Neuraminidase 4 Attenuates Kidney Fibrosis in Mice

Xiao,

Hao,

Kuang

et al. 2024

Advanced Science

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Despite significant progress in therapy, there remains a lack of substantial evidence regarding the molecular factors that lead to renal fibrosis. Neuraminidase 4 (NEU4), an enzyme that removes sialic acids from glycoconjugates, has an unclear role in chronic progressive fibrosis. Here, this study finds that NEU4 expression is markedly upregulated in mouse fibrotic kidneys induced by folic acid or unilateral ureter obstruction, and this elevation is observed in patients with renal fibrosis. NEU4 knockdown specifically in the kidney attenuates the epithelial‐to‐mesenchymal transition, reduces the production of pro‐fibrotic cytokines, and decreases cellular senescence in male mice. Conversely, NEU4 overexpression exacerbates the progression of renal fibrosis. Mechanistically, NEU4254‐388aa interacts with Yes‐associated protein (YAP) at WW2 domain (231‐263aa), promoting its nucleus translocation and activation of target genes, thereby contributing to renal fibrosis. 3,5,6,7,8,3ʹ,4ʹ‐Heptamethoxyflavone, a natural compound, is identified as a novel NEU4 inhibitor, effectively protecting mice from renal fibrosis in a NEU4‐dependent manner. Collectively, the findings suggest that NEU4 may represent a promising therapeutic target for kidney fibrosis.

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Inhibitors of Human Neuraminidase Enzymes Block Transmigration in vitro

Cited by 4 publications

References 46 publications

The extracellular sialidase NEU3 primes neutrophils

The extracellular sialidase NEU3 primes neutrophils

Neuraminidases—Key Players in the Inflammatory Response after Pathophysiological Cardiac Stress and Potential New Therapeutic Targets in Cardiac Disease

Targeting Neuraminidase 4 Attenuates Kidney Fibrosis in Mice

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