Molecular control of physiological and pathological T-cell recruitment after mouse spinal cord injury.
The intraspinal cues that orchestrate T-cell migration and activation after spinal contusion injury were characterized using B10.PL (wild-type) and transgenic (Tg) mice with a T-cell repertoire biased toward recognition of myelin basic protein (MBP). Previously, we showed that these strains exhibit distinct anatomical and behavioral phenotypes. In Tg mice, MBP-reactive T-cells are activated by spinal cord injury (SCI), causing more severe axonal injury, demyelination, and functional impairment than is found in non-Tg wild-type mice (B10.PL). Conversely, despite a robust SCI-induced T-cell response in B10.PL mice, no overt T-cell-mediated pathology was evident. Here, we show that chronic intraspinal T-cell accumulation in B10.PL and Tg mice is associated with a dramatic and sustained increase in CXCL10/IP-10 and CCL5/RANTES mRNA expression. However, in Tg mice, chemokine mRNA were enhanced 2- to 17-fold higher than in B10.PL mice and were associated with accelerated intraspinal T-cell influx and enhanced CNS macrophage activation throughout the spinal cord. These data suggest common molecular pathways for initiating T-cell responses after SCI in mice; however, if T-cell reactions are biased against MBP, molecular and cellular determinants of neuroinflammation are magnified in parallel with exacerbation of neuropathology and functional impairment.
Jones
T Bucky
TB
The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210, USA.
Hart
Ronald P
RP
Popovich
Phillip G
PG
D000818:Animals; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics; D054357:Chemokine CXCL10; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003288:Contusions / Q000276:immunology / Q000473:pathology; D019674:Genes, T-Cell Receptor beta; D006133:Growth Substances / Q000096:biosynthesis* / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics; D053590:Interleukin 1 Receptor Antagonist Protein; D008213:Lymphocyte Activation / Q000276:immunology*; D008222:Lymphokines; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000502:physiology; D004676:Myelin Basic Protein / Q000276:immunology; D009187:Myelitis / Q000209:etiology / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics; D013119:Spinal Cord Injuries / Q000276:immunology* / Q000473:pathology; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1
C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; D006133:Growth Substances; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D008222:Lymphokines; D004676:Myelin Basic Protein; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C092591:fibrosin; D007334:Insulin-Like Growth Factor I