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. 2000 Jul 15;20(14):5283-91.
doi: 10.1523/JNEUROSCI.20-14-05283.2000.

Neuroprotection by encephalomyelitis: rescue of mechanically injured neurons and neurotrophin production by CNS-infiltrating T and natural killer cells

H Hammarberg  1 , O Lidman, C Lundberg, S Y Eltayeb, A W Gielen, S Muhallab, A Svenningsson, H Lindå, P H van Der Meide, S Cullheim, T Olsson, F Piehl
Affiliations

Neuroprotection by encephalomyelitis: rescue of mechanically injured neurons and neurotrophin production by CNS-infiltrating T and natural killer cells

H Hammarberg et al. J Neurosci. .

Abstract

In experimental autoimmune encephalomyelitis (EAE), CD4(+) self-reactive T cells target myelin components of the CNS. However, the consequences of an autoaggressive T cell response against myelin for neurons are currently unknown. We herein demonstrate that EAE induced by active immunization with an encephalitogenic myelin basic protein peptide dramatically reduces the loss of spinal motoneurons after ventral root avulsion in rats. Both brain-derived neurotophic factor (BDNF)- and neurotrophin-3 (NT-3)-like immunoreactivities were detected in mainly T and natural killer (NK) cells in the spinal cord. In addition, very high levels of BDNF, NT-3, and glial cell line-derived neurotrophic factor mRNAs were present in T and NK cell populations infiltrating the CNS. Interestingly, bystander recruited NK and T cells displayed similar or higher neurotrophic factor levels compared with the EAE disease-driving encephalitogenic T cell population. High levels of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) mRNAs were also detected, and both these cytokines can be harmful to several types of CNS cells, including neurons. However, treatment of embryonic motoneuron cultures with TNF-alpha or IFN-gamma only had a deleterious effect in cultures deprived of neurotrophic factors. These results suggest that the potentially neurodamaging consequences of severe CNS inflammation are curbed by the production of several potent neurotrophic factors in leukocytes.

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Figures

Fig. 1.
Fig. 1.
Hematoxylin counterstaining of the L4 segment reveals higher density of small-sized nuclei in the lesioned ventral horn. A, After only ventral root avulsion these nuclei almost entirely consist of proliferating glia (see Results).B, In combination with EAE, the glia proliferation is also accompanied by an extensive infiltration of leukocytes (14 d after immunization). The boxed areas in A andB are shown in higher magnification in Cand D. Note the presence of higher numbers of surviving motoneurons in the immunized animal (C, D, arrowheads). Scale bar, 1 mm.
Fig. 2.
Fig. 2.
Expression of cytokines and neurotrophic factors in spinal cord, lymph nodes, and FACS-sorted cell populations. A, B, Highly elevated mRNA levels of the proinflammatory cytokines TNF-α and IFN-γ are present in the spinal cord of immunized and operated DA rats during active EAE, but not after injury alone. C, Relative quantification of neurotrophin mRNAs demonstrate much higher levels in the spinal cords of immunized animals compared with solely operated animals. D, A moderate induction of GDNF mRNA, but not BDNF and NT-3 mRNAs, is present in lymph nodes from immunized animals. Note differences in the relative levels of neurotrophic factors in lymph nodes and spinal cords. E, Cells sampled from the CNS of LEWRT1L rats during active EAE display highly elevated levels of TNF-α mRNA compared with control cells from lymph nodes of nonimmunized animals. A relatively stronger induction is evident in the TCRBV8S2+ population.F, High levels of neurotrophic factor transcripts are present in leukocyte populations from both immunized and nonimmunized animals. Notably, the TCRBV8S2+ population displays a conspicuous downregulation of the expression of trophic factors compared with the TCRBV10+ and NKR-P1+ populations. EAE,Experimental autoimmune encephalomyelitis; VRA, ventral root avulsion; IL, ipsilateral; CL,contralateral.
Fig. 3.
Fig. 3.
Immunohistochemical colocalization of neurotrophins and leukocyte markers (C, F, I, L, yellow) in spinal cord sections from immunized animals (14 d after immunization) subjected to ventral root avulsion. The depicted cells are located in the ventral horn of the lesioned side. Examples of double-labeled cells are indicated by arrowheads inA–L. The NT-3 immunolabeling displays a high degree of colocalization with W3/25 (CD4+) (A–C), OX8 (CD8+) (D–F), and NKR-P1 (NK cells) (G–I)-labeled cells. The immunolabeling for BDNF is more diffuse and does not colocalize to cells to the same degree as NT-3. However, a moderate number of W3/25-labeled cells also display positive BDNF staining (J–L). Only very weak immunofluorescence is seen in control sections where the primary antibody was pre-absorbed with the corresponding peptide for NT-3 and BDNF, respectively (M and N display double labeling with W3/25). Scale bar, 0.05 mm.
Fig. 4.
Fig. 4.
Dark-field micrographs of the mRNAin situ hybridization labeling pattern for TNF-α (A), BDNF (B), NT-3 (C), and GDNF (D) in draining inguinal lymph nodes from DA rats 14 d after immunization. Arrows indicate single cells with postive labeling. A, TNF-α mRNA is abundantly expressed in activated lymph node cells. B, C, High numbers of BDNF and NT-3 mRNA-positive cells are evident in close adjacent sections of the same area. D, Also GDNF mRNA-positive cells are present in the same area of the lymph node, but detectable expression is restricted to a smaller number of cells. Scale bar, 0.1 mm.
Fig. 5.
Fig. 5.
Effects of IFN-γ and TNF-α on survival of cultured embryonic motoneurons. Cultures were treated with IFN-γ (1, 10, or 100 U/ml) or TNF-α (0.1 or 10 ng/ml). Cytokine treatment did not have any significant effects on the survival of cells cultured in medium supplemented with serum/neurotrophic factors (top graph) or neurotrophic factors alone (middle graph). In contrast, both IFN-γ and TNF-α treatment resulted in a significant, concentration-dependent decrease in numbers of viable cells in cultures deprived of neurotrophic support (bottom graph). Statistical significance was determined with the Kruskall–Wallis test and Dunn's post hoc test against control (*p < 0.05; ***p < 0.001).
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