Siglec-14 Enhances NLRP3-Inflammasome Activation in Macrophages

Tsai, Chuen-Tinn; Riestra, Angelica M.; Ali, Shariq; Fong, Joan; Liu, Janet Z.; Hughes, Gillian; Varki, Ajit; Nizet, Victor

doi:10.1159/000504323

Cited by 42 publications

(27 citation statements)

References 42 publications

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“…Among the Siglec family members, the paired receptors express extremely similar amino acid sequence of extracellular domain and comparable tissue distribution resulting in the same ligand recognition capacity whereas the diverse intracellular signalling pathways trigger the opposite effects. The paired Siglec-5 and Siglec-14 proteins, gene fusion products, are widely expressed on myeloid-derived cells residing and infiltrating human airways, however their distribution in individuals is closely related to the frequencies of wild-type and SIGLEC-14 null alleles in various populations [ 108 , 109 ]. Therefore, the expression of activating Siglec-14 receptor predominates in the European population whereas inhibitory Siglec-5 is widely expressed in Asians.…”

Section: Sialic Acids In Covs Infectionsmentioning

confidence: 99%

Coronaviruses: Is Sialic Acid a Gate to the Eye of Cytokine Storm? From the Entry to the Effects

Wielgat

Rogowski

Godlewska

et al. 2020

Cells

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Coronaviruses (CoVs) are a diverse family of the enveloped human and animal viruses reported as causative agents for respiratory and intestinal infections. The high pathogenic potential of human CoVs, including SARS-CoV, MERS-CoV and SARS-CoV-2, is closely related to the invasion mechanisms underlying the attachment and entry of viral particles to the host cells. There is increasing evidence that sialylated compounds of cellular glycocalyx can serve as an important factor in the mechanism of CoVs infection. Additionally, the sialic acid-mediated cross-reactivity with the host immune lectins is known to exert the immune response of different intensity in selected pathological stages. Here, we focus on the last findings in the field of glycobiology in the context of the role of sialic acid in tissue tropism, viral entry kinetics and immune regulation in the CoVs infections.

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Section: Sialic Acids In Covs Infectionsmentioning

confidence: 99%

Coronaviruses: Is Sialic Acid a Gate to the Eye of Cytokine Storm? From the Entry to the Effects

Wielgat

Rogowski

Godlewska

et al. 2020

Cells

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“…Most recently, it has been demonstrated that NACHT, LRR, and PYD domains-containing protein 3 (NALP3/NLRP3) inflammasome activation plays a vital role in the pathogenesis of tauopathies [ 127 ]. Importantly, SIGLEC-5 reduced NLRP3 inflammasome activation in response to Group B Streptococcus (GBS) infection [ 128 ]. Similarly, GBS β-protein bound SIGLEC-7 to inhibit NLRP3 inflammasome activation and attenuated inflammation in natural killer cells [ 129 ].…”

Section: Sialic Acid (Sia)-related Signaling: Complement Siglecs mentioning

confidence: 99%

Control of Innate Immunity by Sialic Acids in the Nervous Tissue

Liao

Klaus

Neumann

2020

IJMS

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Sialic acids (Sias) are the most abundant terminal sugar residues of glycoproteins and glycolipids on the surface of mammalian cells. The nervous tissue is the organ with the highest expression level of Sias. The ‘sialylation’ of glycoconjugates is performed via sialyltransferases, whereas ‘desialylation’ is done by sialidases or is a possible consequence of oxidative damage. Sialic acid residues on the neural cell surfaces inhibit complement and microglial activation, as well as phagocytosis of the underlying structures, via binding to (i) complement factor H (CFH) or (ii) sialic acid-binding immunoglobulin-like lectin (SIGLEC) receptors. In contrast, activated microglial cells show sialidase activity that desialylates both microglia and neurons, and further stimulates innate immunity via microglia and complement activation. The desialylation conveys neurons to become susceptible to phagocytosis, as well as triggers a microglial phagocytosis-associated oxidative burst and inflammation. Dysfunctions of the ‘Sia–SIGLEC’ and/or ‘Sia–complement’ axes often lead to neurological diseases. Thus, Sias on glycoconjugates of the intact glycocalyx and its desialylation are major regulators of neuroinflammation.

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“…Siglec-5 associates with tyrosine phosphatase SHP-1 to send an inhibitory signal upon ligation, while Siglec-14 associates with the adapter protein DAP-12 and the tyrosine kinase Syk to send an activating signal. Thus Siglec-5 binding downregulates NLRP3 inflammasome activity, while Siglec-14 binding upregulates it [8] , [16] . Importantly, there is a common polymorphism, in which Siglec-14 is replaced by a Siglec-5 like fusion protein (Siglec 14/5) signalling via the inhibitory SHP-1 pathway identically to Siglec-5 [17] .…”

Section: Potential Consequence Of Siglec 14 Null Polymorphism In Covimentioning

confidence: 98%

“…Thus, persons with Siglec-14 Null allele receive an inhibitory input to the NLRP3 inflammasome upon Siglec-5 binding while those without have a stimulatory input, greater in Siglec-14 +/+ homozygotes than heterozygotes ( Fig. 1 ) [16] , [18] . There are recognised functional consequences.…”

Section: Potential Consequence Of Siglec 14 Null Polymorphism In Covimentioning

confidence: 99%

Common determinants of severe Covid-19 infection are explicable by SARS-CoV-2 secreted glycoprotein interaction with the CD33-related Siglecs, Siglec-3 and Siglec-5/14

Murch

2020

Medical Hypotheses

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SARS-CoV-2 interaction with the ACE-2 receptor cannot alone explain the demography and remarkable variation in clinical progression of Covid-19 infection. Unlike SARS-CoV, the cause of SARS, several SARS-CoV-2 spike glycans contain sialic acid residues. In contrast to the SARS secreted glycoprotein (SGP), SARS-CoV-2 SGP are thus potential ligands for Sialic acid-binding Siglecs on host immune cells, known to regulate immune function. Such SARS-CoV-2 glycoproteins would contribute to immune deviation. CD33-related Siglecs are important immune regulators. Siglec-5 and −14 are paired receptors with opposed actions on the NLRP3 inflammasome, which is critical in early viral clearance. SGP binding in persons of Siglec-14 null genotype (30–70% in Black, Asian and Minority Ethnic (BAME) persons, 10% in North Europeans) would induce unopposed inhibitory signalling, causing viral persistence through inflammasome inhibition. Siglec-3 (CD33) and Siglec-5 are expressed on CD33 myeloid derived suppressor cells (CD33 MDSC). Immunosuppressive CD33 MDSC populations are increased in all groups at risk of severe Covid-19 infection. CD33 expression is increased in persons with the CD33 rs3865444 CC allele, associated with Alzheimer’s disease, who would thus show enhanced susceptibility. Viral SGP ligation of CD33, potentially in conjunction with Siglec-5, would promote expansion of CD33 MDSC cells, as occurs in cancers but at much greater scale. CD33 is expressed on CNS microglia, potentially activated by SGP penetration through the porous cribriform plate to cause anosmia. Genotyping of severe or fatal Covid-19 cases can confirm or refute this pathophysiological mechanism. Early data have confirmed extremely high-level increase of CD33 MDSC numbers in severe Covid-19 infection, consistent with the proposed mechanism.

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Siglec-14 Enhances NLRP3-Inflammasome Activation in Macrophages

Cited by 42 publications

References 42 publications

Coronaviruses: Is Sialic Acid a Gate to the Eye of Cytokine Storm? From the Entry to the Effects

Coronaviruses: Is Sialic Acid a Gate to the Eye of Cytokine Storm? From the Entry to the Effects

Control of Innate Immunity by Sialic Acids in the Nervous Tissue

Common determinants of severe Covid-19 infection are explicable by SARS-CoV-2 secreted glycoprotein interaction with the CD33-related Siglecs, Siglec-3 and Siglec-5/14

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