Glial reactivity in ciliary neurotrophic factor-deficient mice after optic nerve lesion.
There is evidence that ciliary neurotrophic factor (CNTF), in addition to its neurotrophic activity, positively regulates astrogliosis after CNS injury. CNTF and its receptor, CNTFRalpha, are strongly upregulated in activated astrocytes. Application of CNTF upregulates GFAP expression in cultured astrocytes and induces various aspects of gliosis in the intact brain. Here we examined whether inactivation of the CNTF gene results in the expected changes in glial reactivity by analyzing gliosis in the superior colliculus (SC) after optic nerve crush. Basal expression levels of GFAP and vimentin in unlesioned CNTF-deficient mice were reduced by 66 and 37%, respectively. Absolute numbers of astrocytes were found not to be different. Surprisingly, however, lesion induced robust activation of astrocytes in CNTF-deficient mice; the time course of activation was even accelerated as compared with wild-type animals. At later time points, activation reached the same level. With respect to microglial cells, basal expression of microglial markers was unaltered in CNTF-knock-out animals. Lesion-induced upregulation of Iba-1, ICAM-1, and F4/80 in microglial cells was unaffected in CNTF-deficient animals. Differences were observed with respect to the time course of microglial activation, different markers being affected differentially. We further demonstrate that lesion induces upregulation of CNTF-related cytokines (LIF, NNT-1) and, interestingly, a more pronounced upregulation of cytokine receptor components (LIF receptor beta, gp130) and TGFbeta in CNTF-deficient animals. Our results thus indicate that CNTF is required for the development and maintenance of the mature astrocyte phenotype and provide evidence that CNTF is part of the complex regulatory network modulating lesional glial reactivity after lesion.
Martin
Aliki
A
Institute of Anatomy, University of Freiburg, D-79001 Freiburg, Germany.
Hofmann
Hans-Dieter
HD
Kirsch
Matthias
M
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D020934:Ciliary Neurotrophic Factor / Q000172:deficiency* / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005911:Gliosis / Q000378:metabolism* / Q000473:pathology; D006131:Growth Inhibitors / Q000378:metabolism; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009409:Nerve Crush; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009900:Optic Nerve / Q000378:metabolism* / Q000473:pathology; D020221:Optic Nerve Injuries / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D013477:Superior Colliculi / Q000378:metabolism / Q000473:pathology
D000943:Antigens, Differentiation; D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D012333:RNA, Messenger; D018121:Receptors, Cytokine