Progranulin Protects Against Exaggerated Axonal Injury and Astrogliosis Following Traumatic Brain Injury

In response to traumatic brain injury (TBI) microglia/macrophages and astrocytes release inflammatory mediators with dual effects on secondary brain damage progression. The neurotrophic and anti-inflammatory glycoprotein progranulin (PGRN) attenuates neuronal damage and microglia/macrophage activation in brain injury but mechanisms are still elusive. Here, we studied histopathology, neurology and gene expression of inflammatory markers in PGRN-deficient mice (Grn(-/-)) 24 h and 5 days after experimental TBI. Grn(-/-) mice displayed increased perilesional axonal injury even though the overall brain tissue loss and neurological consequences were similar to wild-type mice. Brain inflammation was elevated in Grn(-/-) mice as reflected by increased transcription of pro-inflammatory cytokines TNF alpha, IL-1, IL-6, and decreased transcription of the anti-inflammatory cytokine IL-10. However, numbers of Iba1(+) microglia/macrophages and immigrated CD45(+) leukocytes were similar at perilesional sites while determination of IgG extravasation suggested stronger impairment of blood brain barrier integrity in Grn(-/-) compared to wild-type mice. Most strikingly, Grn(-/-) mice displayed exaggerated astrogliosis 5 days after TBI as demonstrated by anti-GFAP immunohistochemistry and immunoblot. GFAP(+) astrocytes at perilesional sites were immunolabelled for iNOS and TNF alpha suggesting that pro-inflammatory activation of astrocytes was attenuated by PGRN. Accordingly, recombinant PGRN (rPGRN) attenuated LPS- and cytokine-evoked iNOS and TNF alpha mRNA expression in cultured astrocytes. Moreover, intracerebroventricular administration of rPGRN immediately before trauma reduced brain damage and neurological deficits, and restored normal levels of cytokine transcription, axonal injury and astrogliosis 5 days after TBI in Grn(-/-) mice. Our results show that endogenous and recombinant PGRN limit axonal injury and astrogliosis and suggest therapeutic potential of PGRN in TBI.