Siglec receptors impact mammalian lifespan by modulating oxidative stress

Schwarz, Flavio; Pearce, Oliver M.T.; Wang, Xiaoxia; Samraj, Annie N.; Läubli, Heinz; Garcia, Javier O.; Lin, Hongqiao; Fu, Xiaoming; Garcia-Bingman, Andrea; Secrest, Patrick; Romanoski, Casey E.; Heyser, Charles J.; Glass, Christopher K.; Hazen, Stanley L.; Varki, Nissi; Varki, Ajit; Gagneux, Pascal

doi:10.7554/elife.06184

Cited by 60 publications

(57 citation statements)

References 73 publications

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“…The results of other studies involving NADPH oxidase-deficient mice confirmed a phagocyte-derived ROS-mediated anti-inflammatory function, which contributes to the suppression of neutrophil recruitment in the lung [64,65]. Schwarz et al [66] speculated that Siglec-E evolved in mammals because it helped control ROS levels during chronic inflammation. However, McMillan et al [13] demonstrated that Siglec-E affects ROS homeostasis.…”

Section: Siglec-e As An Inhibitor Of Neutrophil Recruitmentsupporting

confidence: 50%

Targeting Neutrophils in Severe Asthma via Siglec-9

Chen

Bai

Han

et al. 2018

Int Arch Allergy Immunol

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Severe asthma comprises only 5% of patients with asthma, but the burden it brings to the social health system accounts for more than half of all asthmatics. Clinical evidence shows that severe asthma is often linked to the recruitment and activation of neutrophils in the airways. However, the underlying molecular and immunological mechanisms of neutrophilia in severe asthma are not clear and currently available drugs exert only limited effects on neutrophilic inflammation. Great efforts are underway to address the mystery of neutrophilic inflammation in chronic respiratory disorders. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are members of the immunoglobulin gene family. Of note, Siglec-9 is uniquely expressed by human neutrophils and monocytes, as well as a minor population of natural killer cells. Engaging this structure with antibodies or glycan ligands results in programmed cell death in human neutrophils. Intriguingly, the administration of Siglec-E antibody abolished the recruitment of neutrophils in mouse models of neutrophilic pulmonary inflammation in vivo. Given that neutrophils are probably a major culprit in the generation and perpetuation of inflammation, targeting Siglec-9 could be beneficial for the treatment of severe asthma, chronic obstructive pulmonary disease, and related pulmonary disorders characteristic of neutrophilia.

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Section: Siglec-e As An Inhibitor Of Neutrophil Recruitmentsupporting

confidence: 50%

Targeting Neutrophils in Severe Asthma via Siglec-9

Chen

Bai

Han

et al. 2018

Int Arch Allergy Immunol

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“…The proposed link between bat longevity, viral tolerance and antiinflammatory response is certainly plausible also in the light of available evidence from other species. Number of anti-inflammatory CD33rSiglec family genes shown strong positive correlation with maximum life span in 14 mammalian species (Schwarz et al, 2015) and longer life spans of laboratory rat strains have been linked with maintaining ability to synthesize not only proinflammatory TNF, but also anti-inflammatory Il-10 (Dimitrijević et al, 2014). Interestingly, increased production of Il-10 promotes viral persistence (Brooks et al, 2006) and higher levels of serum Il-10 are associated with asymptomatic infections in humans (Guiyedi et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

A Potent Anti-Inflammatory Response in Bat Macrophages May Be Linked to Extended Longevity and Viral Tolerance

Kacprzyk

Hughes

Pålsson-McDermott

et al. 2017

Acta Chiropterologica

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Bats are unique among mammals given their ability to fly, apparent tolerance of deadly viruses and extraordinary longevity. We propose that these traits are linked and driven by adaptations of the innate immune system. To explore this hypothesis we challenged macrophages from the greater mouse-eared bat, Myotis myotis and the house mouse, Mus musculus with Toll Like Receptors (TLRs) ligands, lipopolysaccharides, LPS and polyinosinic-polycytidylic acid, Poly(I:C). Macrophages from both species presented a high level of mRNA induction of inferon β (INF-β), tumor necrosis factor (TNF) and interleukin-1β (Il-1β). However, in bat macrophages, this antiviral, proinflammatory response was balanced by a sustained high-level transcription of the anti-inflammatory cytokine Il-10, which was not observed in mouse, potentially resulting from adaptive regulation in bats.Additionally, phylogenomic selection tests across the basal divergences in mammals (n = 39) uncovered bat-specific adaptations in six genes involved in antiviral and proinflammatory signalling. Based on this pilot study, we put forward a hypothesis that bats may have evolved unique anti-inflammatory responses to neutralize proinflammatory stimuli resulting from flight. This in turn may drive their extraordinary longevity and viral tolerance by limiting inflammation driven ageing and infection-induced immunopathology. Further data from other individuals and bat species are required to advance this intriguing hypothesis.

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“…Removal of sialic acids with sialidase Neu1 can disrupt this interaction, resulting in activation of inflammatory processes. LPS stimulation induces exaggerated recruitment of neutrophils in the lung in Siglec-E knock-out mice (14,15). In mouse models of bacterial infection (16), tumor growth (17), and sepsis (18), Siglec-E plays a critical role in the pathogenesis of diseases.…”

Section: Cd33-related Siglecs Are a Family Of Proteins Widely Expressmentioning

confidence: 99%

“…In mouse models of bacterial infection (16), tumor growth (17), and sepsis (18), Siglec-E plays a critical role in the pathogenesis of diseases. Siglec-E also modulates oxidative stress that leads to aging (15).…”

Section: Cd33-related Siglecs Are a Family Of Proteins Widely Expressmentioning

confidence: 99%

“…Some commercially available antibodies have been used to detect Siglec-E in transfected Chinese hamster ovary (CHO) cells (19) and mouse microglia (20). Polyclonal Siglec-E antibody from R&D Systems (goat anti-Siglec-E) has been used in multiple studies (15)(16)(17). In a recent study, Siglec-E antibody was used to block the interaction of Siglec-E with sialylated ligands (18).…”

Section: Cd33-related Siglecs Are a Family Of Proteins Widely Expressmentioning

confidence: 99%

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Studies on the Detection, Expression, Glycosylation, Dimerization, and Ligand Binding Properties of Mouse Siglec-E

Siddiqui

Schwarz

Springer

et al. 2017

Journal of Biological Chemistry

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Edited by Amanda F. Fosang CD33-related Siglecs are a family of proteins widely expressed on innate immune cells. Binding of sialylated glycans or other ligands triggers signals that inhibit or activate inflammation.Immunomodulation by Siglecs has been extensively studied, but relationships between structure and functions are poorly explored. Here we present new data relating to the structure and function of Siglec-E, the major CD33-related Siglec expressed on mouse neutrophils, monocytes, macrophages, and dendritic cells. We generated nine new rat monoclonal antibodies specific to mouse Siglec-E, with no cross-reactivity to Siglec-F. Although all antibodies detected Siglec-E on transfected human HEK-293T cells, only two reacted with mouse bone marrow neutrophils by flow cytometry and on spleen sections by immunohistochemistry. Moreover, whereas all antibodies recognized Siglec-E-Fc on immunoblots, binding was dependent on intact disulfide bonds and N-glycans, and only two antibodies recognized native Siglec-E within spleen lysates. Thus, we further investigated the impact of Siglec-E homodimerization. Homology-based structural modeling predicted a cysteine residue (Cys-298) in position to form a disulfide bridge between two Siglec-E polypeptides. Mutagenesis of Cys-298 confirmed its role in dimerization. In keeping with the high level of 9-O-acetylation found in mice, sialoglycan array studies indicate that this modification has complex effects on recognition by Siglec-E, in relationship to the underlying structures. However, we found no differences in phosphorylation or SHP-1 recruitment between dimeric and monomeric Siglec-E expressed on HEK293A cells. Phylogenomic analyses predicted that only some human and mouse Siglecs form disulfide-linked dimers. Notably, Siglec-9, the functionally equivalent human paralog of Siglec-E, occurs as a monomer. Two broad groups of Siglecs are identified based on their patterns of evolution. Sialoadhesin, CD22, myelin-associated glycoprotein (MAG) and Siglec-15 are highly conserved and show few changes among species (2). In contrast, CD33-related Siglecs evolve rapidly in mammals (2, 9). As there are not clear functional orthologs between primates and rodent Siglecs, these receptors are assigned an alphabetic letter in rodents and a number in primates. Siglec-E, the main CD33-related Siglec in mouse, was first discovered by a yeast two-hybrid screen using SHP-1 as a bait (10). Studies using a sheep polyclonal Siglec-E antibody specific for the ectodomain indicated that Siglec-E is expressed on neutrophils, macrophages, monocytes, dendritic cells, and a subset of Natural killer cells (11). The organ with the * This work was supported, in whole or in part, by National Institutes of Health Grants P01HL107150 and R01GM32373 (to A. V.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. □ S Th...

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Siglec receptors impact mammalian lifespan by modulating oxidative stress

Cited by 60 publications

References 73 publications

Targeting Neutrophils in Severe Asthma via Siglec-9

Targeting Neutrophils in Severe Asthma via Siglec-9

A Potent Anti-Inflammatory Response in Bat Macrophages May Be Linked to Extended Longevity and Viral Tolerance

Studies on the Detection, Expression, Glycosylation, Dimerization, and Ligand Binding Properties of Mouse Siglec-E

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