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Age-Related Gene Expression Differences in Monocytes from Human Neonates, Young Adults, and Older Adults.

Lissner MM, Thomas BJ, Wee K, Tong AJ, Kollmann TR, Smale ST - PLoS ONE (2015)

Bottom Line: A variety of age-related differences in the innate and adaptive immune systems have been proposed to contribute to the increased susceptibility to infection of human neonates and older adults.By examining the differentially induced genes in the context of transcription factor binding motifs and RNA-seq data sets from mutant mouse strains, a previously described deficiency in interferon response factor-3 activity could be implicated in most of the differences between newborns and young adults.Contrary to these observations, older adults exhibited elevated expression of inflammatory genes at baseline, yet the responses following stimulation correlated more closely with those observed in younger adults.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.

ABSTRACT
A variety of age-related differences in the innate and adaptive immune systems have been proposed to contribute to the increased susceptibility to infection of human neonates and older adults. The emergence of RNA sequencing (RNA-seq) provides an opportunity to obtain an unbiased, comprehensive, and quantitative view of gene expression differences in defined cell types from different age groups. An examination of ex vivo human monocyte responses to lipopolysaccharide stimulation or Listeria monocytogenes infection by RNA-seq revealed extensive similarities between neonates, young adults, and older adults, with an unexpectedly small number of genes exhibiting statistically significant age-dependent differences. By examining the differentially induced genes in the context of transcription factor binding motifs and RNA-seq data sets from mutant mouse strains, a previously described deficiency in interferon response factor-3 activity could be implicated in most of the differences between newborns and young adults. Contrary to these observations, older adults exhibited elevated expression of inflammatory genes at baseline, yet the responses following stimulation correlated more closely with those observed in younger adults. Notably, major differences in the expression of constitutively expressed genes were not observed, suggesting that the age-related differences are driven by environmental influences rather than cell-autonomous differences in monocyte development.

No MeSH data available.


Related in: MedlinePlus

Elevated expression of a broad range of inflammatory genes prior to stimulation of freshly isolated monocytes from older adults.(A) LPS-induced genes exhibiting differential basal expression between adults and older adults (n = 189) are grouped according to maximum mRNA level. Columns 7 and 8 show the ratio of transcript levels between older adults and young adults before stimulation and at maximum transcript levels, respectively. (B) The average relative transcript levels within each cluster and for each age are shown.
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pone.0132061.g007: Elevated expression of a broad range of inflammatory genes prior to stimulation of freshly isolated monocytes from older adults.(A) LPS-induced genes exhibiting differential basal expression between adults and older adults (n = 189) are grouped according to maximum mRNA level. Columns 7 and 8 show the ratio of transcript levels between older adults and young adults before stimulation and at maximum transcript levels, respectively. (B) The average relative transcript levels within each cluster and for each age are shown.

Mentions: To evaluate gene expression differences between young adults and older adults, we first used the strategy described above to identify differentially induced genes. This analysis revealed smaller differences in transcriptional induction than were observed when comparing the neonatal and young adult profiles (data not shown), suggesting that the pathways involved in the responses to LPS and Lm in monocytes in young adults and older adults are highly similar. Instead, the largest differences were observed when examining transcript levels for inducible genes prior to stimulation. Specifically, 189 LPS-induced genes (>5-fold induction magnitude; induction significance p<0.01; maximum induced transcript level >4 RPKM) exhibited transcript levels that were significantly different (p<0.01) in unstimulated cells from young adults in comparison to older adults (Fig 7A; gene list in S3 Fig). For these 189 genes, Fig 7A, column 7 shows the ratio of the unstimulated transcript level in older adults to that in younger adults (OA0/A0). In this figure, the genes are grouped on the basis of their time point of maximum expression, and the genes were then rank-ordered by the ratio of the unstimulated transcript level. This analysis revealed that a large majority of the differentially expressed genes are expressed at an elevated level in unstimulated cells from older adults (shown as shades of red, see vertical color scale at right). In fact, 52% of the differentially expressed genes exhibited unstimulated transcript levels in older adults that were at least 3-fold higher than in young adults, whereas only 3% exhibited transcript levels that were at least 3-fold higher in young adults than in older adults. Similar results were observed in the Lm experiment (data not shown), but the number of genes showing differential expression was lower, probably because the unstimulated cells for the Lm experiment were cultured for 2 hrs prior to collection, whereas the unstimulated cells in the LPS experiment were collected without culturing.


Age-Related Gene Expression Differences in Monocytes from Human Neonates, Young Adults, and Older Adults.

Lissner MM, Thomas BJ, Wee K, Tong AJ, Kollmann TR, Smale ST - PLoS ONE (2015)

Elevated expression of a broad range of inflammatory genes prior to stimulation of freshly isolated monocytes from older adults.(A) LPS-induced genes exhibiting differential basal expression between adults and older adults (n = 189) are grouped according to maximum mRNA level. Columns 7 and 8 show the ratio of transcript levels between older adults and young adults before stimulation and at maximum transcript levels, respectively. (B) The average relative transcript levels within each cluster and for each age are shown.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4493075&req=5

pone.0132061.g007: Elevated expression of a broad range of inflammatory genes prior to stimulation of freshly isolated monocytes from older adults.(A) LPS-induced genes exhibiting differential basal expression between adults and older adults (n = 189) are grouped according to maximum mRNA level. Columns 7 and 8 show the ratio of transcript levels between older adults and young adults before stimulation and at maximum transcript levels, respectively. (B) The average relative transcript levels within each cluster and for each age are shown.
Mentions: To evaluate gene expression differences between young adults and older adults, we first used the strategy described above to identify differentially induced genes. This analysis revealed smaller differences in transcriptional induction than were observed when comparing the neonatal and young adult profiles (data not shown), suggesting that the pathways involved in the responses to LPS and Lm in monocytes in young adults and older adults are highly similar. Instead, the largest differences were observed when examining transcript levels for inducible genes prior to stimulation. Specifically, 189 LPS-induced genes (>5-fold induction magnitude; induction significance p<0.01; maximum induced transcript level >4 RPKM) exhibited transcript levels that were significantly different (p<0.01) in unstimulated cells from young adults in comparison to older adults (Fig 7A; gene list in S3 Fig). For these 189 genes, Fig 7A, column 7 shows the ratio of the unstimulated transcript level in older adults to that in younger adults (OA0/A0). In this figure, the genes are grouped on the basis of their time point of maximum expression, and the genes were then rank-ordered by the ratio of the unstimulated transcript level. This analysis revealed that a large majority of the differentially expressed genes are expressed at an elevated level in unstimulated cells from older adults (shown as shades of red, see vertical color scale at right). In fact, 52% of the differentially expressed genes exhibited unstimulated transcript levels in older adults that were at least 3-fold higher than in young adults, whereas only 3% exhibited transcript levels that were at least 3-fold higher in young adults than in older adults. Similar results were observed in the Lm experiment (data not shown), but the number of genes showing differential expression was lower, probably because the unstimulated cells for the Lm experiment were cultured for 2 hrs prior to collection, whereas the unstimulated cells in the LPS experiment were collected without culturing.

Bottom Line: A variety of age-related differences in the innate and adaptive immune systems have been proposed to contribute to the increased susceptibility to infection of human neonates and older adults.By examining the differentially induced genes in the context of transcription factor binding motifs and RNA-seq data sets from mutant mouse strains, a previously described deficiency in interferon response factor-3 activity could be implicated in most of the differences between newborns and young adults.Contrary to these observations, older adults exhibited elevated expression of inflammatory genes at baseline, yet the responses following stimulation correlated more closely with those observed in younger adults.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.

ABSTRACT
A variety of age-related differences in the innate and adaptive immune systems have been proposed to contribute to the increased susceptibility to infection of human neonates and older adults. The emergence of RNA sequencing (RNA-seq) provides an opportunity to obtain an unbiased, comprehensive, and quantitative view of gene expression differences in defined cell types from different age groups. An examination of ex vivo human monocyte responses to lipopolysaccharide stimulation or Listeria monocytogenes infection by RNA-seq revealed extensive similarities between neonates, young adults, and older adults, with an unexpectedly small number of genes exhibiting statistically significant age-dependent differences. By examining the differentially induced genes in the context of transcription factor binding motifs and RNA-seq data sets from mutant mouse strains, a previously described deficiency in interferon response factor-3 activity could be implicated in most of the differences between newborns and young adults. Contrary to these observations, older adults exhibited elevated expression of inflammatory genes at baseline, yet the responses following stimulation correlated more closely with those observed in younger adults. Notably, major differences in the expression of constitutively expressed genes were not observed, suggesting that the age-related differences are driven by environmental influences rather than cell-autonomous differences in monocyte development.

No MeSH data available.


Related in: MedlinePlus