Central nervous system inflammation and neurological disease in transgenic mice expressing the CC chemokine CCL21 in oligodendrocytes.
To study the biological role of the chemokine ligands CCL19 and CCL21, we generated transgenic mice expressing either gene in oligodendrocytes of the CNS. While all transgenic mice expressing CCL19 in the CNS developed normally, most (18 of 26) of the CCL21 founder mice developed a neurological disease that was characterized by loss of landing reflex, tremor, and ataxia. These neurological signs were observed as early as postnatal day 9 and were associated with weight loss and death during the first 4 wk of life. Microscopic examination of the brain and spinal cord of CCL21 transgenic mice revealed scattered leukocytic infiltrates that consisted primarily of neutrophils and eosinophils. Additional findings included hypomyelination, spongiform myelinopathy with evidence of myelin breakdown, and reactive gliosis. Thus, ectopic expression of the CC chemokine CCL21, but not CCL19, induced a significant inflammatory response in the CNS. However, neither chemokine was sufficient to recruit lymphocytes into the CNS. These observations are in striking contrast to the reported activities of these molecules in vitro and may indicate specific requirements for their biological activity in vivo.
Chen
Shu-Cheng
SC
Department of Immunology, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Leach
Michael W
MW
Chen
Yuetian
Y
Cai
Xiao-Yan
XY
Sullivan
Lee
L
Wiekowski
Maria
M
Dovey-Hartman
B J
BJ
Zlotnik
Albert
A
Lira
Sergio A
SA
D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002493:Central Nervous System Diseases / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D002531:Cerebellum / Q000473:pathology; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D018925:Chemokines / Q000096:biosynthesis; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D003711:Demyelinating Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005911:Gliosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007962:Leukocytes / Q000473:pathology; D008526:Medulla Oblongata / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D009836:Oligodendroglia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D013116:Spinal Cord / Q000473:pathology
C515461:Ccl19 protein, mouse; C515479:Ccl21c protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D018925:Chemokines; D019742:Chemokines, CC; D016207:Cytokines; D004676:Myelin Basic Protein