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Progranulin Protects Hippocampal Neurogenesis via Suppression of Neuroinflammatory Responses Under Acute Immune Stress

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Abstract

Immune stress is well known to suppress adult neurogenesis in the hippocampus. We have demonstrated that progranulin (PGRN) has a mitogenic effect on neurogenesis under several experimental conditions. We have also shown that PGRN suppresses excessive neuroinflammatory responses after traumatic brain injury. However, the role of PGRN in modulating neurogenesis under acute immune stress is yet to be elucidated. In the present study, we evaluated the involvement of PGRN in neurogenesis and inflammatory responses in the hippocampus using a lipopolysaccharide (LPS)-induced immune stress model. Treatment of mice with LPS significantly increased the expression of PGRN in activated microglia and decreased neurogenesis in the dentate gyrus of the hippocampus. PGRN deficiency increased CD68-immunoreactive area and exacerbated suppression of neurogenesis following LPS treatment. The expression levels of lysosomal genes including lysozyme M, macrophage expressed gene 1, and cathepsin Z were higher in PGRN-deficient than in wild-type mice, while PGRN deficiency decreased mammalian target of rapamycin (mTOR) mRNA levels, suggesting that PGRN suppresses excessive lysosomal biogenesis by promoting mTOR signaling. LPS treatment also increased the expression of proinflammatory genes such as interleukin (IL)-1β, tumor necrosis factor-α, and microsomal prostaglandin E synthase-1 (mPGES-1) in the hippocampus, and PGRN deficiency further enhanced gene expression of IL-6 and mPGES-1. These results suggest that PGRN plays a protecting role in hippocampal neurogenesis at least partially by attenuating neuroinflammatory responses during LPS-induced acute immune stress.

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Abbreviations

ANOVA:

Analysis of variance

BrdU:

Bromodeoxyuridine

CNS:

Central nervous system

COX-2:

Cyclooxygenase-2

Ctsz:

Cathepsin Z

DCX:

Doublecortin

DG:

Dentate gyrus

GCL:

Granule cell layer

HPRT:

Hypoxanthine phosphoribosyltransferase

HSD:

Honestly significant difference

Iba-1:

Ionized calcium-binding adapter molecule 1

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

i.p.:

Intraperitoneally

KO:

GRN-deficient

LAMP1:

Lysosomal-associated membrane protein 1

LPS:

Lipopolysaccharide

Lyz2:

Lysozyme M

Mpeg1:

Macrophage expressed gene 1

mPGES-1:

Microsomal prostaglandin E synthase-1

mTOR:

Mammalian target of rapamycin

NPCs:

Neural progenitor cells

PBS:

Phosphate-buffered saline

PGRN:

Progranulin

PGE2:

Prostaglandin E2

RT:

Reverse transcription

SGZ:

Subgranular zone

TBI:

Traumatic brain injury

TNF-α:

Tumor necrosis factor-α

WT:

Wild-type

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Acknowledgements

This work was partly supported by JSPS KAKENHI (Grant Number 23228004 to MN) and a JSPS Postdoctoral Fellowship for Foreign Researchers (Grant Number 26.04906 to YM).

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Correspondence to Masugi Nishihara.

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Ma, Y., Matsuwaki, T., Yamanouchi, K. et al. Progranulin Protects Hippocampal Neurogenesis via Suppression of Neuroinflammatory Responses Under Acute Immune Stress. Mol Neurobiol 54, 3717–3728 (2017). https://doi.org/10.1007/s12035-016-9939-6

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