Progranulin (PGRN), encoded by the GRN gene, is a potent neurotrophic and anti-inflammatory factor expressed by neurons and microglia. Heterozygous or homozygous loss-of-function mutations in the human GRN gene cause frontotemporal dementia and neuronal ceroid lipofuscinosis, respectively. Previous studies also demonstrated exacerbated consequences in Grn-deficient mice after experimental traumatic brain injury (TBI). However, the relative contribution of neuronal or microglial PGRN in neuroprotective and anti-inflammatory effects is still elusive. Here, we tested the hypothesis that transgenic Nestin-Cre driven Grn expression on Grn-deficient background (Nestin-GrnGrn-/-) rescues exacerbated consequences after experimental TBI.Three groups of adult male mice (Grn+/+, Nestin-GrnGrn-/-, and Grn-/- ,all C57BL/6J background, n=6-12/group) were subjected to experimental TBI and examined for key parameters of brain histopathology and inflammation at 5 days post injury. Differences between all groups were calculated dependent on data distribution by one-way ANOVA or Kruskal-Wallis test followed by post hoc tests.Grn mRNA expression in Nestin-GrnGrn-/- mice was substantially lower than in Grn+/+ mice but slightly higher than in Grn-/- mice. Determination of brain lesion volume, loss of hippocampal neurons, inflammatory marker mRNA expression (Aif1, Cd68, Gfap, Lyz2, Spp1, Tnfa) and microglial lipid accumulation confirmed exacerbated TBI pathology in Grn-/- mice compared to WT. Nestin-GrnGrn-/- mice showed a smaller brain lesion volume, reduced loss of hippocampal neurons, and mitigated perilesional brain tissue infiltration by CD68+ microglia along with reduced Cd68 expression compared to Grn-/- mice. Our results show that even low levels of Nestin-Cre-mediated Grn expression rescues excacerbated brain damage and microglial activation in Grn-/- mice