Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice

Fangfang Yin., et al. The Journal of Experimental Medicine 18:117-28 (2010)

Speaker: Chih-Cheng Kang (康智程)                             Time: 13:10~14:00, Apr 21, 2010

Commentator: Dr. Shun-hua Chen (陳舜華 老師)      Place: Room 601

Abstract:

Progranulin (PGRN) is a pluripotent glycoprotein which involves in cell growth, proliferation, wound repair and inflammation. PGRN is expressed by epithelial cells, macrophages, and neurons. Researchers revealed that mutations in the PGRN gene causes a neurodegenerative brain diseases, frontotemporal dementia (FTD). FTD is the second most common dementia in people under the age of 65 characterized by shrinkage of the frontal and temporal lobes of the brain. However, the mechanisms of PGRN involved in FTD are still unknown. Therefore, the authors investigated the role of PGRN by generating PGRN-deficient mice. The authors demonstrated the expression level of proinflammatory cytokines and chemokines were higher and the anti-inflammation cytokine IL-10 was lower in LPS challenged PGRN-deficient macrophages than in WT macrophages. Subsequently, PGRN-deficient mice infected with Listeria monocytogenes shown a higher level of MCP-1 in circulation, spleen and brain than those in WT. However, the infiltration of monocytes into spleen and the clearance of bacteria in spleen, liver and brain were all decreased in deficient mice. On the other hand, the activation of microglia and astrocytes in the brain of aged PGRN-deficient mice was observed. PGRN-deficient macrophages are more potent in killing hippocampus cells than WT macrophages, especially after stimulation with LPS and IFN-g. Furthermore, the ubiquitination and phosphorylation of transactivation response element DNA binding protein-43 (TDP-43) were increased in the brain of PGRN-deficient mice. Thus, this study demonstrate that PGRN play a key role in both host defense and neuronal integrity, suggesting that FTD associated with deficiency ofPGRN may result from dysregulated inflammation and the cumulative neuronal damage in the brain.

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