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

被引：46

作者：

Raj, Divya D. A. ^{[1
]}

Moser, Jill ^{[2
,3
]}

van der Pol, Susanne M. A. ^{[4
]}

van Os, Ronald P. ^{[5
]}

Holtman, Inge R. ^{[1
]}

Brouwer, Nieske ^{[1
]}

Oeseburg, Hisko ^{[6
]}

Schaafsma, Wandert ^{[1
]}

Wesseling, Evelyn M. ^{[1
]}

den Dunnen, Wilfred ^{[3
]}

Biber, Knut P. H. ^{[1
,7
]}

de Vries, Helga E. ^{[4
]}

Eggen, Bart J. L. ^{[1
]}

Boddeke, Hendrikus W. G. M. ^{[1
]}

机构：

[1] Univ Groningen, Univ Med Ctr Groningen, Dept Neurosci, Sect Med Physiol, NL-9713 AV Groningen, Netherlands

[2] Univ Groningen, Univ Med Ctr Groningen, Dept Crit Care, NL-9713 AV Groningen, Netherlands

[3] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, NL-9713 AV Groningen, Netherlands

[4] Vrije Univ Amsterdam Med Ctr, Dept Mol Cell Biol & Immunol, Blood Brain Barrier Res Grp, Neurosci Campus Amsterdam, NL-1007 MB Amsterdam, Netherlands

[5] Univ Groningen, Univ Med Ctr Groningen, European Res Inst Biol Aging, Dept Cell Biol, NL-9713 AV Groningen, Netherlands

[6] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 AV Groningen, Netherlands

[7] Univ Med Ctr, Dept Psychiat & Psychotherapy, D-79104 Freiburg, Germany

来源：

AGING CELL | 2015年 / 14卷 / 06期

关键词：

aging; blood-brain barrier; microglia; neuroimmune; response; priming; telomere; telomerase; GENE-EXPRESSION; SENESCENCE; PROLIFERATION; MONOCYTES; LONGEVITY; PATHOLOGY; LENGTH; STATES; ROLES; VITRO;

D O I：

10.1111/acel.12370

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1003 / 1013

页数：11

共 54 条

[1] Local self-renewal can sustain CNS microglia maintenance and function throughout adult life [J].