Open AccessEnhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening
Author(s) -
Raj Divya D. A.,
Moser Jill,
Pol Susanne M. A.,
Os Ronald P.,
Holtman Inge R.,
Brouwer Nieske,
Oeseburg Hisko,
Schaafsma Wandert,
Wesseling Evelyn M.,
Dunnen Wilfred,
Biber Knut P. H.,
Vries Helga E.,
Eggen Bart J. L.,
Boddeke Hendrikus W. G. M.
Publication year - 2015
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12370
Subject(s) - microglia , biology , inflammation , lipopolysaccharide , telomere , telomerase , immunology , innate immune system , immune system , parenchyma , gene , genetics , botany
Summary 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 G 1 mT erc −/− )‐ and late‐generation (third‐generation G 3 and G 4 mT erc −/− ) telomerase‐deficient mice, which carry a homozygous deletion for the telomerase RNA component gene ( mT erc ). Late‐generation mT erc −/− microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G 3 mT erc −/− microglia are comparable with microglia derived from G 1 mT erc −/− mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide ( LPS ), G 3 mT erc −/− 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.