Limits...
Siglec receptors impact mammalian lifespan by modulating oxidative stress.

Schwarz F, Pearce OM, Wang X, Samraj AN, Läubli H, Garcia JO, Lin H, Fu X, Garcia-Bingman A, Secrest P, Romanoski CE, Heyser C, Glass CK, Hazen SL, Varki N, Varki A, Gagneux P - Elife (2015)

Bottom Line: In this study, we report evidence of a significant correlation between the number of genes encoding the immunomodulatory CD33-related sialic acid-binding immunoglobulin-like receptors (CD33rSiglecs) and maximum lifespan in mammals.We found that accelerated aging was related both to an unbalanced ROS metabolism, and to a secondary impairment in detoxification of reactive molecules, ultimately leading to increased damage to cellular DNA, proteins, and lipids.Taken together, our data suggest that CD33rSiglecs co-evolved in mammals to achieve a better management of oxidative stress during inflammation, which in turn reduces molecular damage and extends lifespan.

View Article: PubMed Central - PubMed

Affiliation: Glycobiology Research and Training Center, University of California, San Diego, San Diego, United States.

ABSTRACT
Aging is a multifactorial process that includes the lifelong accumulation of molecular damage, leading to age-related frailty, disability and disease, and eventually death. In this study, we report evidence of a significant correlation between the number of genes encoding the immunomodulatory CD33-related sialic acid-binding immunoglobulin-like receptors (CD33rSiglecs) and maximum lifespan in mammals. In keeping with this, we show that mice lacking Siglec-E, the main member of the CD33rSiglec family, exhibit reduced survival. Removal of Siglec-E causes the development of exaggerated signs of aging at the molecular, structural, and cognitive level. We found that accelerated aging was related both to an unbalanced ROS metabolism, and to a secondary impairment in detoxification of reactive molecules, ultimately leading to increased damage to cellular DNA, proteins, and lipids. Taken together, our data suggest that CD33rSiglecs co-evolved in mammals to achieve a better management of oxidative stress during inflammation, which in turn reduces molecular damage and extends lifespan.

Show MeSH

Related in: MedlinePlus

Neutrophils lacking Siglec-E are more prone to oxidative burst.Neutrophils isolated from bone marrow were incubated with immunocomplexes conjugated with a probe sensitive to ROS. Flow cytometry profiles at 60 min indicate that cells lacking Siglec-E are more prone to produce ROS, whereas the levels of ROS are comparably low before stimulation. Gates indicate cells producing ROS.DOI:http://dx.doi.org/10.7554/eLife.06184.017
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4384638&req=5

fig3s1: Neutrophils lacking Siglec-E are more prone to oxidative burst.Neutrophils isolated from bone marrow were incubated with immunocomplexes conjugated with a probe sensitive to ROS. Flow cytometry profiles at 60 min indicate that cells lacking Siglec-E are more prone to produce ROS, whereas the levels of ROS are comparably low before stimulation. Gates indicate cells producing ROS.DOI:http://dx.doi.org/10.7554/eLife.06184.017

Mentions: Siglec-E regulates inflammatory states upon acute stress (McMillan et al., 2013; Chang et al., 2014). We speculated that aging might act as a chronic stimulus and investigated whether Siglec-E−/− mice exhibited low-grade signs of inflammation. As noted above, some organs showed accumulation of inflammatory cells (Figure 2—figure supplement 5). Inflammation was not due to anti-nuclear antibodies, which are typical of some autoimmune diseases but were undetectable in the sera of Siglec-E−/− and WT mice. To gain mechanistic insights, we analyzed the role of Siglec-E on the management of oxidative stress in innate immune cells. Primary bone marrow neutrophils from Siglec-E−/− mice were more prone to produce oxidative burst upon stimulation, compared to controls (Figure 3A and Figure 3—figure supplement 1). Additionally, neutrophils lacking Siglec-E secreted higher ROS per cell (Figure 3B). Similarly, thioglycollate-recruited peritoneal neutrophils showed a 10% increase in ROS (Figure 3—figure supplement 2), corroborating the notion that Siglec-E controls oxidative stress and that the elimination of CD33rSiglec receptors leads to disordered ROS. These observations were also in line with what was shown with a microglial cell line (Claude et al., 2013).10.7554/eLife.06184.016Figure 3.Altered ROS homeostasis in mice lacking Siglec-E.


Siglec receptors impact mammalian lifespan by modulating oxidative stress.

Schwarz F, Pearce OM, Wang X, Samraj AN, Läubli H, Garcia JO, Lin H, Fu X, Garcia-Bingman A, Secrest P, Romanoski CE, Heyser C, Glass CK, Hazen SL, Varki N, Varki A, Gagneux P - Elife (2015)

Neutrophils lacking Siglec-E are more prone to oxidative burst.Neutrophils isolated from bone marrow were incubated with immunocomplexes conjugated with a probe sensitive to ROS. Flow cytometry profiles at 60 min indicate that cells lacking Siglec-E are more prone to produce ROS, whereas the levels of ROS are comparably low before stimulation. Gates indicate cells producing ROS.DOI:http://dx.doi.org/10.7554/eLife.06184.017
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384638&req=5

fig3s1: Neutrophils lacking Siglec-E are more prone to oxidative burst.Neutrophils isolated from bone marrow were incubated with immunocomplexes conjugated with a probe sensitive to ROS. Flow cytometry profiles at 60 min indicate that cells lacking Siglec-E are more prone to produce ROS, whereas the levels of ROS are comparably low before stimulation. Gates indicate cells producing ROS.DOI:http://dx.doi.org/10.7554/eLife.06184.017
Mentions: Siglec-E regulates inflammatory states upon acute stress (McMillan et al., 2013; Chang et al., 2014). We speculated that aging might act as a chronic stimulus and investigated whether Siglec-E−/− mice exhibited low-grade signs of inflammation. As noted above, some organs showed accumulation of inflammatory cells (Figure 2—figure supplement 5). Inflammation was not due to anti-nuclear antibodies, which are typical of some autoimmune diseases but were undetectable in the sera of Siglec-E−/− and WT mice. To gain mechanistic insights, we analyzed the role of Siglec-E on the management of oxidative stress in innate immune cells. Primary bone marrow neutrophils from Siglec-E−/− mice were more prone to produce oxidative burst upon stimulation, compared to controls (Figure 3A and Figure 3—figure supplement 1). Additionally, neutrophils lacking Siglec-E secreted higher ROS per cell (Figure 3B). Similarly, thioglycollate-recruited peritoneal neutrophils showed a 10% increase in ROS (Figure 3—figure supplement 2), corroborating the notion that Siglec-E controls oxidative stress and that the elimination of CD33rSiglec receptors leads to disordered ROS. These observations were also in line with what was shown with a microglial cell line (Claude et al., 2013).10.7554/eLife.06184.016Figure 3.Altered ROS homeostasis in mice lacking Siglec-E.

Bottom Line: In this study, we report evidence of a significant correlation between the number of genes encoding the immunomodulatory CD33-related sialic acid-binding immunoglobulin-like receptors (CD33rSiglecs) and maximum lifespan in mammals.We found that accelerated aging was related both to an unbalanced ROS metabolism, and to a secondary impairment in detoxification of reactive molecules, ultimately leading to increased damage to cellular DNA, proteins, and lipids.Taken together, our data suggest that CD33rSiglecs co-evolved in mammals to achieve a better management of oxidative stress during inflammation, which in turn reduces molecular damage and extends lifespan.

View Article: PubMed Central - PubMed

Affiliation: Glycobiology Research and Training Center, University of California, San Diego, San Diego, United States.

ABSTRACT
Aging is a multifactorial process that includes the lifelong accumulation of molecular damage, leading to age-related frailty, disability and disease, and eventually death. In this study, we report evidence of a significant correlation between the number of genes encoding the immunomodulatory CD33-related sialic acid-binding immunoglobulin-like receptors (CD33rSiglecs) and maximum lifespan in mammals. In keeping with this, we show that mice lacking Siglec-E, the main member of the CD33rSiglec family, exhibit reduced survival. Removal of Siglec-E causes the development of exaggerated signs of aging at the molecular, structural, and cognitive level. We found that accelerated aging was related both to an unbalanced ROS metabolism, and to a secondary impairment in detoxification of reactive molecules, ultimately leading to increased damage to cellular DNA, proteins, and lipids. Taken together, our data suggest that CD33rSiglecs co-evolved in mammals to achieve a better management of oxidative stress during inflammation, which in turn reduces molecular damage and extends lifespan.

Show MeSH
Related in: MedlinePlus