title: Lack of NG2 exacerbates neurological outcome and modulates glial responses after traumatic brain injury.
abstract: Traumatic brain injury (TBI) is a major cause of death and disability. The underlying pathophysiology is characterized by secondary processes including neuronal death and gliosis. To elucidate the role of the NG2 proteoglycan we investigated the response of NG2-knockout mice (NG2-KO) to TBI. Seven days after TBI behavioral analysis, brain damage volumetry and assessment of blood brain barrier integrity demonstrated an exacerbated response of NG2-KO compared to wild-type (WT) mice. Reactive astrocytes and expression of the reactive astrocyte and neurotoxicity marker Lcn2 (Lipocalin-2) were increased in the perilesional brain tissue of NG2-KO mice. In addition, microglia/macrophages with activated morphology were increased in number and mRNA expression of the M2 marker Arg1 (Arginase 1) was enhanced in NG2-KO mice. While TBI-induced expression of pro-inflammatory cytokine genes was unchanged between genotypes, PCR array screening revealed a marked TBI-induced up-regulation of the C-X-C motif chemokine 13 gene Cxcl13 in NG2-KO mice. CXCL13, known to attract immune cells to the inflamed brain, was expressed by activated perilesional microglia/macrophages seven days after TBI. Thirty days after TBI, NG2-KO mice still exhibited more pronounced neurological deficits than WT mice, up-regulation of Cxcl13, enhanced CD45+ leukocyte infiltration and a relative increase of activated Iba-1+/CD45+ microglia/macrophages. Our study demonstrates that lack of NG2 exacerbates the neurological outcome after TBI and associates with abnormal activation of astrocytes, microglia/macrophages and increased leukocyte recruitment to the injured brain. These findings suggest that NG2 may counteract neurological deficits and adverse glial responses in TBI.
authors.affiliation: Department of Anesthesiology, University Medical Center, Johannes Gutenberg-University Mainz, Germany.
authors.forename: Changsheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Biology, Molecular Cell Biology, Johannes Gutenberg-University Mainz, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Sakry
authors.affiliation: Department of Anesthesiology, University Medical Center, Johannes Gutenberg-University Mainz, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Menzel
authors.affiliation: Department of Anesthesiology, University Medical Center, Johannes Gutenberg-University Mainz, Germany.
authors.forename: Larissa
authors.initials: L
authors.lastname: Dangel
authors.affiliation: Department of Anesthesiology, University Medical Center, Johannes Gutenberg-University Mainz, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Sebastiani
authors.affiliation: Department of Anesthesiology, University Medical Center, Johannes Gutenberg-University Mainz, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Krämer
authors.affiliation: Department of Biology, Molecular Cell Biology, Johannes Gutenberg-University Mainz, Germany.|Institute for Molecular Medicine, University Medical Center, Johannes Gutenberg-University Mainz, Germany.
authors.forename: Khalad
authors.initials: K
authors.lastname: Karram
authors.affiliation: Department of Anesthesiology, University Medical Center, Johannes Gutenberg-University Mainz, Germany.|Focus Program Translational Neurosciences (FTN) of the Johannes Gutenberg-University Mainz, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Engelhard
authors.affiliation: Department of Biology, Molecular Cell Biology, Johannes Gutenberg-University Mainz, Germany.|Focus Program Translational Neurosciences (FTN) of the Johannes Gutenberg-University Mainz, Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Trotter
authors.affiliation: Department of Anesthesiology, University Medical Center, Johannes Gutenberg-University Mainz, Germany.|Focus Program Translational Neurosciences (FTN) of the Johannes Gutenberg-University Mainz, Germany.
authors.forename: Michael K E
authors.initials: MK
authors.lastname: Schäfer
mesh_terms: D000818:Animals; D000941:Antigens / Q000235:genetics / Q000378:metabolism*; D001119:Arginase / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002199:Capillary Permeability / Q000502:physiology; D002452:Cell Count; D002478:Cells, Cultured; D054382:Chemokine CXCL13 / Q000378:metabolism; D015331:Cohort Studies; D004195:Disease Models, Animal; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D001119:Arginase; D002135:Calcium-Binding Proteins; D054382:Chemokine CXCL13; D017493:Leukocyte Common Antigens; D008840:Microfilament Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D000099216:Chondroitin Sulfate Proteoglycan 4; C491049:Aif1 protein, mouse; C486386:Cxcl13 protein, mouse; C516770:Ptprc protein, mouse; C544448:Arg1 protein, mouse
keywords: CNS inflammation; Cxcl13; astrocytes; gliosis; macrophages; microglia