Exacerbated inflammatory responses related to activated microglia after traumatic brain injury in progranulin-deficient mice

Neuroscience. 2013 Feb 12:231:49-60. doi: 10.1016/j.neuroscience.2012.11.032. Epub 2012 Nov 29.


Progranulin (PGRN), a multifunctional growth factor, appears to play a role in neurodegenerative diseases accompanied by neuroinflammation. In this study, we investigated the role of PGRN in neuroinflammation, especially in the activation of microglia, by means of experimental traumatic brain injury (TBI) in the cerebral cortex of mice. The expression of GRN mRNA was increased in association with neuroinflammation after TBI. Double-immunohistochemical study showed that PGRN-immunoreactive (-IR) cells were mainly overlapped with CD68-IR cells, suggesting that the main source of PGRN was CD68-positive activated microglia. To investigate the role of PGRN in inflammatory responses related to activated microglia, we compared the immunoreactivity and expression of ionized calcium-binding adaptor molecule 1 (Iba1), CD68, and CD11b as markers for activated microglia between wild-type (WT) and GRN-deficient (KO) mice. The number of Iba1- and CD11b-IR cells and gene expression of Iba1 and CD11b were not significantly different between WT and KO mice, while the number of CD68-IR cells and CD68 expression in KO mice were significantly greater than those in WT mice. Double-immunohistochemical study showed that CD68-IR microglia were also IR for TGFβ1, and TGFβ1 expression and Smad3 phosphorylation in KO mice were elevated compared to WT mice. Moreover, double-immunostaining between phospho-Smad3 and glial fibrillary acidic protein suggested increased TGFβ1-Smad3 signal mainly by astrocytes. The levels of protein carbonyl groups, which reflect protein oxidation, and laminin immunoreactivity, which is associated with angiogenesis, were also significantly increased in KO mice compared to WT mice. These results suggest that PGRN is produced in CD68-positive microglia and suppresses excessive inflammatory responses related to activated microglia after TBI in mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / genetics
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Astrocytes / metabolism
  • Brain Injuries / metabolism
  • Brain Injuries / pathology*
  • Brain Injuries / physiopathology
  • CD11b Antigen / genetics
  • CD11b Antigen / metabolism
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cerebral Cortex / injuries*
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Glial Fibrillary Acidic Protein / metabolism
  • Granulins
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Inflammation / physiopathology
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Microglia / metabolism*
  • Phosphorylation
  • Progranulins
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism


  • Aif1 protein, mouse
  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD11b Antigen
  • CD68 protein, mouse
  • Calcium-Binding Proteins
  • Glial Fibrillary Acidic Protein
  • Granulins
  • Grn protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Microfilament Proteins
  • Progranulins
  • Smad3 Protein
  • Transforming Growth Factor beta1