Neuroinflammation by cytotoxic T-lymphocytes impairs retrograde axonal transport in an oligodendrocyte mutant mouse. PLoS One 2012;7(8):e42554
Date
08/21/2012Pubmed ID
22905147Pubmed Central ID
PMC3414455DOI
10.1371/journal.pone.0042554Scopus ID
2-s2.0-84864705710 (requires institutional sign-in at Scopus site) 30 CitationsAbstract
Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage.
Author List
Ip CW, Kroner A, Groh J, Huber M, Klein D, Spahn I, Diem R, Williams SK, Nave KA, Edgar JM, Martini RAuthor
Antje Kroner-Milsch MD, PhD Associate Professor in the Neurosurgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAxons
Bone Marrow Transplantation
CD8-Positive T-Lymphocytes
Granzymes
Heterozygote
Immune System
Inflammation
Mice
Mice, Transgenic
Mutation
Neurons
Oligodendroglia
Proteolipids
Retinal Ganglion Cells
T-Lymphocytes, Cytotoxic
