TLR9 signalling in microglia attenuates seizure-induced aberrant neurogenesis in the adult hippocampus

Taito Matsuda; Naoya Murao; Yuki Katano; Berry Juliandi; Jun Kohyama; Shizuo Akira; Taro Kawai; Kinichi Nakashima

doi:10.1038/ncomms7514

TLR9 signalling in microglia attenuates seizure-induced aberrant neurogenesis in the adult hippocampus

Nat Commun. 2015 Mar 9:6:6514. doi: 10.1038/ncomms7514.

Authors

Taito Matsuda¹, Naoya Murao², Yuki Katano², Berry Juliandi³, Jun Kohyama⁴, Shizuo Akira⁵, Taro Kawai⁶, Kinichi Nakashima¹

Affiliations

¹ Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
² 1] Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan [2] Laboratory of Gene Regulation Research, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), Nara 630-0192, Japan.
³ 1] Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan [2] Department of Biology, Bogor Agricultural University, Bogor 16144, Indonesia.
⁴ Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
⁵ 1] Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan [2] Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
⁶ Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, NAIST, Nara 630-0192, Japan.

Abstract

Pathological conditions such as epilepsy cause misregulation of adult neural stem/progenitor populations in the adult hippocampus in mice, and the resulting abnormal neurogenesis leads to impairment in learning and memory. However, how animals cope with abnormal neurogenesis remains unknown. Here we show that microglia in the mouse hippocampus attenuate convulsive seizure-mediated aberrant neurogenesis through the activation of Toll-like receptor 9 (TLR9), an innate immune sensor known to recognize microbial DNA and trigger inflammatory responses. We found that microglia sense self-DNA from degenerating neurons following seizure, and secrete tumour necrosis factor-α, resulting in attenuation of aberrant neurogenesis. Furthermore, TLR9 deficiency exacerbated seizure-induced cognitive decline and recurrent seizure severity. Our findings thus suggest the existence of bidirectional communication between the innate immune and nervous systems for the maintenance of adult brain integrity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cognition
Cognitive Dysfunction / genetics
Cognitive Dysfunction / immunology*
Cognitive Dysfunction / pathology
Gene Expression Regulation
Hippocampus / growth & development
Hippocampus / immunology*
Hippocampus / metabolism
Hippocampus / pathology
Immunity, Innate / genetics
Male
Membrane Glycoproteins / deficiency
Membrane Glycoproteins / genetics
Membrane Glycoproteins / immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Microglia / immunology*
Microglia / metabolism
Microglia / pathology
Neurogenesis / genetics
Neurogenesis / immunology*
Neurons / immunology
Neurons / metabolism
Neurons / pathology
Seizures / genetics
Seizures / immunology*
Seizures / metabolism
Seizures / pathology
Severity of Illness Index
Signal Transduction / genetics
Signal Transduction / immunology
Toll-Like Receptor 7 / deficiency
Toll-Like Receptor 7 / genetics
Toll-Like Receptor 7 / immunology
Toll-Like Receptor 9 / deficiency
Toll-Like Receptor 9 / genetics*
Toll-Like Receptor 9 / immunology
Tumor Necrosis Factor-alpha / genetics
Tumor Necrosis Factor-alpha / immunology
Tumor Necrosis Factor-alpha / metabolism

Substances

Membrane Glycoproteins
Tlr7 protein, mouse
Tlr9 protein, mouse
Toll-Like Receptor 7
Toll-Like Receptor 9
Tumor Necrosis Factor-alpha