Neutrophil infiltration, glial reaction, and neurological disease in transgenic mice expressing the chemokine N51/KC in oligodendrocytes.
Chemokines (pro-inflammatory chemoattractant cytokines) are expressed in pathological conditions of the central nervous system (CNS). Previous studies suggested that the CNS is relatively resistant to leukocyte diapedesis after chemokine injection, leaving their functional role unresolved. The CNS function of N51/KC, a neutrophil-selective chemokine, was addressed by expressing N51/KC under control of the myelin basic protein (MBP) promoter in transgenic (tg) mice (MBP-N51/KC mice). CNS-specific N51/KC expression produced remarkable neutrophil infiltration into perivascular, meningeal, and parenchymal sites, demonstrating that this chemokine exerts the multiple functions in vivo required to recruit leukocytes into the CNS. MBP-N5 1/KC mice represent an incisive model for the molecular dissection of neutrophil entry into the CNS. Unexpectedly, MBP-N51/KC mice developed a neurological syndrome of pronounced postural instability and rigidity at high frequency beginning at 40 days of age, well after peak chemokine expression. 68/182 mice in one tg fine were found dead before one year of age, with prominent neurological symptoms premortem in 26 (38%). Florid microglial activation and blood-brain barrier disruption without dysmyelination were the major neuropathological alterations. Late-onset neurological symptoms in MBP-N51/KC mice may indicate unanticipated consequences of CNS chemokine expression.
Tani
M
M
Department of Neurosciences, Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Fuentes
M E
ME
Peterson
J W
JW
Trapp
B D
BD
Durham
S K
SK
Loy
J K
JK
Bravo
R
R
Ransohoff
R M
RM
Lira
S A
SA
D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001483:Base Sequence; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D017931:DNA Primers; D005260:Female; D006133:Growth Substances / Q000096:biosynthesis* / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D007438:Introns; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000096:biosynthesis / Q000235:genetics; D009422:Nervous System Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D009457:Neuroglia / Q000473:pathology / Q000502:physiology*; D009504:Neutrophils / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D009836:Oligodendroglia / Q000473:pathology / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011187:Posture; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015183:Restriction Mapping
D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; D016207:Cytokines; D017931:DNA Primers; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D004676:Myelin Basic Protein; D011993:Recombinant Fusion Proteins; C074302:keratinocyte-derived chemokines