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

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.Progranulin (PGRN), also known as proepithelin, acrogranin, or prostate cancer cell–derived growth factor (He and Bateman, 2003), is a secreted protein that undergoes proteolysis to generate seven mutually homologous 6-kD peptides, called GRNs or epithelins. Cysteine comprises 88 of PGRN’s 593 residues and forms six intramolecular disulfide bridges in each of the GRNs, giving them a compact globular structure (Tolkatchev et al., 2008). PGRN is expressed by epithelial cells, macrophages, and neurons. Expression analyses and experiments with the native or recombinant protein have implicated PGRN in embryonic development, tumorigenesis, and wound healing (Daniel et al., 2000; Zhu et al., 2002; He and Bateman, 2003). A prominent role of PGRN in the regulation of inflammation was suggested by our discovery that neutrophil elastase and macrophage-derived secretory leukocyte protease inhibitor (SLPI) promote and prevent, respectively, the conversion of PGRN to GRNs, and that recombinant PGRN inhibits neutrophil activation, whereas GRNs promote epithelial cell generation of neutrophil chemoattractants (Zhu et al., 2002).Mutations in the PGRN gene were recently found to cause frontotemporal dementia (FTD), the second most common dementia in people under the age of 65 (Neary et al., 1998). FTD patients experience gradual and progressive changes in behavior and personality, followed by a cognitive decline, prominent language disorders, and sometimes Parkinsonism, in association with progressive cortical atrophy, neuronal loss, astrocytic gliosis, and microglial activation (Neary et al., 1998). At least 66 different pathogenic mutations in the PGRN gene have been documented in FTD patients, all of which resulted in functional null alleles and haploinsufficiency. These were associated with ubiqitinopathies, characterized by the deposit of ubiquitin-positive but tau-negative immunoreactivity in neuronal cytoplasmic and neuronal intranuclear inclusions (Mackenzie et al., 2006; Cairns et al., 2007; Josephs et al., 2007). One component of neuronal inclusions from PGRN-linked FTD patients was identified as transactivation response element DNA binding protein–43 (TDP-43; Neumann et al., 2006). Recent studies have linked pathological redistribution of TDP-43 from nuclei to cytoplasm to its phosphorylation and degradation (Cook et al., 2008; Hasegawa et al., 2008).In this paper, we report that PGRN-deficient mice responded to infection with exaggerated inflammation. In vitro, their macrophages responded to microbial products by expressing enhanced levels of proinflammatory mediators and reduced antiinflammatory IL-10. Ex vivo, PGRN-deficient hippocampal neurons were more vulnerable than WT to metabolic stress. Finally, we detected microgliosis, astrocytosis, and cytoplasmic localization and phosphorylation of TDP-43 in the hippocampus and thalamus in aged PGRN-deficient mice but not in their WT counterparts. Thus, PGRN has a nonredundant role in modulating inflammatory responses. Our studies raise the possibility that FTD may result in part from brain damage arising from the combination of dysregulated inflammation and heightened neuronal vulnerability.