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 den Dunnen; 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 den Dunnen, 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 › peer-review

48 Scopus citations

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 pro-inflammatory 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 (US)
Pages (from-to)	1003-1013
Number of pages	11
Journal	Aging Cell
Volume	14
Issue number	6
DOIs	https://doi.org/10.1111/acel.12370
State	Published - Dec 1 2015
Externally published	Yes

Funding

Funding Part of the work has been performed at the UMCG microscopy and imaging center (UMIC), which is sponsored by NWO-grants 40-00506- 98-9021 and 175-010-2009-023. Help with morphometry imaging by Klaas Sjollema is acknowledged. Operators of central FACS facility of UMCG, Geert Mesander, Henk Moes, and Roelof Jan van der Lei, are acknowledged for their support. The research leading to these results has received funding from the European Community''s Seventh Framework Programme (FP7/2007-2013) under grant agreement No. HEALTHF2- 2010- 259893. KB was supported by the German Research Council (DFG): FOR1336, grant numbers L: DFG BI 668/5-1, BI668/2-2. This work was also supported by the Mouse Clinic for Cancer and Aging through a RoadMap grant from the Netherlands Organization for Scientific Research (NWO). The authors greatly acknowledge Dr. Pim van der Harst, Dr. Herman Silljé, Dr. Liza S. M. Wong, and Inge Vreeswijk- Baudoin of the Dept of Cardiology, UMCG, for help with the mTerc mouse colony. B6. Cg-Tg (CAG-DsRed* MST)1Nagy/J (dsRed) transgenic mice was a kind gift from Dr. Gerald de Haan''s laboratory.

Keywords

Aging
Blood-brain barrier
Microglia
Neuroimmune response
Priming
Telomerase
Telomere

ASJC Scopus subject areas

Aging
Cell Biology

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10.1111/acel.12370

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., den Dunnen, 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

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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 pro-inflammatory 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, Telomerase, Telomere",

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 {den Dunnen}, Wilfred and Biber, {Knut P.H.} and {de Vries}, {Helga E.} and Eggen, {Bart J.L.} and Boddeke, {Hendrikus W.G.M.}",

note = "Publisher Copyright: {\textcopyright} 2015 The Anatomical Society and John Wiley & Sons Ltd.",

year = "2015",

month = dec,

day = "1",

doi = "10.1111/acel.12370",

language = "English (US)",

volume = "14",

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Raj, DDA, Moser, J, van der Pol, SMA, van Os, RP, Holtman, IR, Brouwer, N, Oeseburg, H, Schaafsma, W, Wesseling, EM, den Dunnen, 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, 01.12.2015, p. 1003-1013.

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

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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 - den Dunnen, Wilfred

AU - Biber, Knut P.H.

AU - de Vries, Helga E.

AU - Eggen, Bart J.L.

AU - Boddeke, Hendrikus W.G.M.

PY - 2015/12/1

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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 pro-inflammatory 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 pro-inflammatory 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.

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KW - Blood-brain barrier

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KW - Priming

KW - Telomerase

KW - Telomere

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

Abstract

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ASJC Scopus subject areas

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