Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening

Divya  D.A. Raj; Jill Moser; Susanne M. A. van der Pol; Ronald P. van Os; Inge R. Holtman; Nieske Brouwer; Hisko Oeseburg; Wandert Schaafsma; Evelyn M. Wesseling; Wilfred Dunnen, den; Knut P. H. Biber; Helga E. de Vries; Bart J. L. Eggen; Hendrikus W. G. M. Boddeke

doi:10.1111/acel.12370

Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening

Divya D.A. Raj, Jill Moser, Susanne M. A. van der Pol, Ronald P. van Os, Inge R. Holtman, Nieske Brouwer, Hisko Oeseburg, Wandert Schaafsma, Evelyn M. Wesseling, Wilfred Dunnen, den, Knut P. H. Biber, Helga E. de Vries, Bart J. L. Eggen, Hendrikus W. G. M. Boddeke^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

49 Citations (Scopus)

523 Downloads (Pure)

Abstract

Microglia are a proliferative population of resident brain macrophages that under physiological conditions self-renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as 'priming'. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first-generation G1 mTerc(-/-))- and late-generation (third-generation G3 and G4 mTerc(-/-)) telomerase-deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late-generation mTerc(-/-) microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc(-/-) microglia are comparable with microglia derived from G1 mTerc(-/-) mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc(-/-) microglia mice show an enhanced proinflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age-associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood-brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening.

Original language	English
Pages (from-to)	1003-1013
Number of pages	11
Journal	Aging Cell
Volume	14
Issue number	6
Early online date	3-Aug-2015
DOIs	https://doi.org/10.1111/acel.12370
Publication status	Published - Dec-2015

Keywords

aging
blood-brain barrier
microglia
neuroimmune
response
priming
telomere
telomerase
ALZHEIMERS-DISEASE
CELL SENESCENCE
GENE-EXPRESSION
IN-VIVO
MICE
CNS
NEURODEGENERATION
PROLIFERATION
MONOCYTES
LONGEVITY

Access to Document

10.1111/acel.12370Licence: CC BY

Raj_et_al_2015_Aging_CellFinal publisher's version, 1.65 MBLicence: CC BY
Raj_et_al-2015-Aging_CellFinal publisher's version, 3.38 MB

Handle.net

Persistent link

Cite this

Raj, D. D. A., Moser, J., van der Pol, S. M. A., van Os, R. P., Holtman, I. R., Brouwer, N., Oeseburg, H., Schaafsma, W., Wesseling, E. M., Dunnen, den, W., Biber, K. P. H., de Vries, H. E., Eggen, B. J. L., & Boddeke, H. W. G. M. (2015). Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening. Aging Cell, 14(6), 1003-1013. https://doi.org/10.1111/acel.12370

@article{230263e1f40e44d092f9cf7eed03b73c,

title = "Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening",

abstract = "Microglia are a proliferative population of resident brain macrophages that under physiological conditions self-renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as 'priming'. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first-generation G1 mTerc(-/-))- and late-generation (third-generation G3 and G4 mTerc(-/-)) telomerase-deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late-generation mTerc(-/-) microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc(-/-) microglia are comparable with microglia derived from G1 mTerc(-/-) mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc(-/-) microglia mice show an enhanced proinflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age-associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood-brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening.",

keywords = "aging, blood-brain barrier, microglia, neuroimmune, response, priming, telomere, telomerase, ALZHEIMERS-DISEASE, CELL SENESCENCE, GENE-EXPRESSION, IN-VIVO, MICE, CNS, NEURODEGENERATION, PROLIFERATION, MONOCYTES, LONGEVITY",

author = "Raj, {Divya D.A.} and Jill Moser and {van der Pol}, {Susanne M. A.} and {van Os}, {Ronald P.} and Holtman, {Inge R.} and Nieske Brouwer and Hisko Oeseburg and Wandert Schaafsma and Wesseling, {Evelyn M.} and {Dunnen, den}, Wilfred and Biber, {Knut P. H.} and {de Vries}, {Helga E.} and Eggen, {Bart J. L.} and Boddeke, {Hendrikus W. G. M.}",

note = "{\textcopyright} 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.",

year = "2015",

month = dec,

doi = "10.1111/acel.12370",

language = "English",

volume = "14",

pages = "1003--1013",

journal = "Aging Cell",

issn = "1474-9718",

publisher = "Wiley",

number = "6",

}

Raj, DDA, Moser, J, van der Pol, SMA, van Os, RP , Holtman, IR , Brouwer, N, Oeseburg, H, Schaafsma, W, Wesseling, EM , Dunnen, den, W, Biber, KPH, de Vries, HE, Eggen, BJL & Boddeke, HWGM 2015, 'Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening', Aging Cell, vol. 14, no. 6, pp. 1003-1013. https://doi.org/10.1111/acel.12370

Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening. / Raj, Divya D.A.; Moser, Jill; van der Pol, Susanne M. A. et al.
In: Aging Cell, Vol. 14, No. 6, 12.2015, p. 1003-1013.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening

AU - Raj, Divya D.A.

AU - Moser, Jill

AU - van der Pol, Susanne M. A.

AU - van Os, Ronald P.

AU - Holtman, Inge R.

AU - Brouwer, Nieske

AU - Oeseburg, Hisko

AU - Schaafsma, Wandert

AU - Wesseling, Evelyn M.

AU - Dunnen, den, Wilfred

AU - Biber, Knut P. H.

AU - de Vries, Helga E.

AU - Eggen, Bart J. L.

AU - Boddeke, Hendrikus W. G. M.

PY - 2015/12

Y1 - 2015/12

N2 - Microglia are a proliferative population of resident brain macrophages that under physiological conditions self-renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as 'priming'. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first-generation G1 mTerc(-/-))- and late-generation (third-generation G3 and G4 mTerc(-/-)) telomerase-deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late-generation mTerc(-/-) microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc(-/-) microglia are comparable with microglia derived from G1 mTerc(-/-) mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc(-/-) microglia mice show an enhanced proinflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age-associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood-brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening.

AB - Microglia are a proliferative population of resident brain macrophages that under physiological conditions self-renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as 'priming'. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first-generation G1 mTerc(-/-))- and late-generation (third-generation G3 and G4 mTerc(-/-)) telomerase-deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late-generation mTerc(-/-) microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc(-/-) microglia are comparable with microglia derived from G1 mTerc(-/-) mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc(-/-) microglia mice show an enhanced proinflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age-associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood-brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening.

KW - aging

KW - blood-brain barrier

KW - microglia

KW - neuroimmune

KW - response

KW - priming

KW - telomere

KW - telomerase

KW - ALZHEIMERS-DISEASE

KW - CELL SENESCENCE

KW - GENE-EXPRESSION

KW - IN-VIVO

KW - MICE

KW - CNS

KW - NEURODEGENERATION

KW - PROLIFERATION

KW - MONOCYTES

KW - LONGEVITY

U2 - 10.1111/acel.12370

DO - 10.1111/acel.12370

M3 - Article

C2 - 26238505

SN - 1474-9718

VL - 14

SP - 1003

EP - 1013

JO - Aging Cell

JF - Aging Cell

IS - 6

ER -

Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening

Abstract

Keywords

Access to Document

Handle.net

Fingerprint

Cite this