Selective depletion of microglial progranulin in mice is not sufficient to cause neuronal ceroid lipofuscinosis or neuroinflammation

Background: progranulin deficiency due to heterozygous null mutations in the grn gene are a common cause of familial frontotemporal lobar degeneration (ftld),while homozygous loss-of-function grn mutations are thought to be a rare cause of neuronal ceroid lipofuscinosis (ncl). aged progranulin-knockout (grn-null) mice display highly exaggerated lipofuscinosis,microgliosis,and astrogliosis,as well as mild cell loss in specific brain regions. in the brain,progranulin is predominantly expressed in neurons and microglia,and previously,we demonstrated that neuronal-specific depletion of progranulin does not recapitulate the neuropathological phenotype of grn-null mice. in this study,we evaluated whether selective depletion of progranulin expression in myeloid-lineage cells,including microglia,causes ncl-like neuropathology or neuroinflammation in mice. methods: we generated mice with progranulin depleted in myeloid-lineage cells by crossing mice homozygous for a floxed progranulin allele to mice expressing cre recombinase under control of the lyzm promotor (lyz-cko). results: progranulin expression was reduced by approximately 50-70% in isolated microglia compared to wt levels. lyz-cko mice aged to 12months did not display any increase in lipofuscin deposition,microgliosis,or astrogliosis in the four brain regions examined,though increases were observed for many of these measures in grn-null animals. to evaluate the functional effect of reduced progranulin expression in isolated microglia,primary cultures were stimulated with controlled standard endotoxin and cytokine release was measured. while grn-null microglia display a hyper-inflammatory phenotype,lyz-cko and wt microglia secreted similar levels of inflammatory cytokines. conclusion: we conclude that progranulin expression from either microglia or neurons is sufficient to prevent the development of ncl-like neuropathology in mice. furthermore,microglia that are deficient for progranulin expression but isolated from a progranulin-rich environment have a normal inflammatory profile. our results suggest that progranulin acts,at least partly,in a non-cell autonomous manner in the brain. © 2017 the author(s).