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Author(s): Yin FF (Yin, Fangfang); Banerjee R (Banerjee, Rebecca); Thomas B (Thomas, Bobby); Zhou P (Zhou, Ping); Qian LP (Qian, Liping); Jia T (Jia, Ting); Ma XJ (Ma, Xiaojing); Ma Y (Ma, Yao); Iadecola C (Iadecola, Costantino); Beal MF (Beal, M. Flint); Nathan C (Nathan, Carl); Ding AH (Ding, Aihao)
Title: Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice
Source: JOURNAL OF EXPERIMENTAL MEDICINE 207 (1): 117-128
Date: 2010 JAN 18
Document Type: Journal : Article
DOI: 10.1084/jem.20091568
Language: English
Comment:
Address: Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY 10065 USA.
Weill Cornell Med Coll, Dept Neurol & Neurosci, New York, NY 10065 USA. Weill Cornell Med Coll, Div Neurobiol, New York, NY 10065 USA. Cornell Univ, Weill Grad Sch Med Sci, Grad Program Immunol & Microbial Pathogenesis, New York, NY 10065 USA. Chinese Acad Med Sci, Inst Mat Med, Beijing 100050, Peoples R China. Reprint: Ding, AH, Weill Cornell Med Coll, Dept Microbiol & Immunol, New York,
NY 10065 USA. E-mail: ahding@med.cornell.edu
Author Keywords:
KeyWords Plus: FRONTOTEMPORAL LOBAR DEGENERATION; AMYOTROPHIC-LATERAL-SCLEROSIS;
NEURONAL SURVIVAL; ALZHEIMER-DISEASE; GROWTH-FACTOR; TDP-43; GENE;
EXPRESSION; INCLUSIONS; MUTATIONS
Abstract: Progranulin (PGRN) is a widely expressed protein involved in diverse biological processes. Haploinsufficiency of PGRN in the human causes tau-negative, ubiquitin-positive frontotemporal dementia (FTD). However, the mechanisms are unknown. To explore the role of PGRN in vivo, we generated PGRN-deficient mice. Macrophages from these mice released less interleukin-10 and more inflammatory cytokines than wild type (WT) when exposed to bacterial lipopolysaccharide. PGRN-deficient mice failed to clear Listeria monocytogenes infection as quickly as WT and allowed bacteria to proliferate in the brain, with correspondingly greater inflammation than in WT. PGRN-deficient macrophages and microglia were cytotoxic to hippocampal cells in vitro, and PGRN-deficient hippocampal slices were hypersusceptible to deprivation of oxygen and glucose. With age, brains of PGRN-deficient mice displayed greater activation of microglia and astrocytes than WT, and their hippocampal and thalamic neurons accumulated cytosolic phosphorylated transactivation response element DNA binding protein-43. Thus, PGRN is a key regulator of inflammation and plays critical roles in both host defense and neuronal integrity. FTD associated with PGRN insufficiency may result from many years of reduced neutrotrophic support together with cumulative damage in association with dysregulated inflammation.
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