Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice
| Autor: | Rebecca Banerjee, Fangfang Yin, Yao Ma, Costantino Iadecola, Ting Jia, Liping Qian, Carl Nathan, Xiaojing Ma, Ping Zhou, M. Flint Beal, Aihao Ding, Bobby Thomas |
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| Rok vydání: | 2009 |
| Předmět: |
Aging
Lipopolysaccharide medicine.medical_treatment Immunology Inflammation Biology Hippocampal formation Hippocampus Article Brain Ischemia Proinflammatory cytokine Mice 03 medical and health sciences chemistry.chemical_compound Transactivation Progranulins 0302 clinical medicine medicine Animals Humans Immunology and Allergy Listeriosis Granulins 030304 developmental biology Mice Knockout 0303 health sciences Microglia Macrophages Listeria monocytogenes Interleukin-10 3. Good health Interleukin 10 medicine.anatomical_structure Cytokine chemistry Astrocytes Frontotemporal Dementia Intercellular Signaling Peptides and Proteins medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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