The myelin-associated protein Nogo-A has received more research attention than any other inhibitor of axonal regeneration in the injured central nervous system (CNS). Circumvention of its inhibitory effect, by using antibodies specific to Nogo-A, has been shown to promote axonal regrowth. Studies in our laboratory have demonstrated that active or passive immunization of CNS-injured rats or mice with myelin-associated peptides induces a T-cell-mediated protective autoimmune response, which promotes recovery by reducing posttraumatic degeneration. Here, we show that neuronal degeneration after incomplete spinal-cord contusion in rats was substantially reduced, and hence recovery was significantly promoted, by posttraumatic immunization with p472, a peptide derived from Nogo-A. The observed effect seemed to be mediated by T cells and could be reproduced by passive transfer of a T cell line directed against the Nogo-A peptide. Thus, it seems that after incomplete spinal-cord injury, immunization with a variety of myelin-associated peptides, including those derived from Nogo-A, can be used to evoke a T cell-mediated response that promotes recovery. The choice of peptide(s) for clinical treatment of spinal-cord injuries should be based on safety considerations; in particular, the likelihood that the chosen peptide will not cause an autoimmune disease or interfere with essential functions of this peptide or other proteins. From a therapeutic point of view, the fact that the active cellular agents are T cells rather than antibodies is an advantage, as T cell production commences within the time window required for a protective effect after spinal-cord injury, whereas antibody production takes longer.
Accumulating evidence suggests that activation of the immune system in the central nervous system (CNS) after trauma protects the CNS from damage propagation and facilitates regeneration. Studies by our group have shown that passive transfer of autoimmune T cells specific to myelin basic protein (T(MBP)) can protect injured neurons in the rat CNS from secondary degeneration. In this study, we investigated the effects of T(MBP) treatment on the local immune response (by B cells and macrophages) and on the expression of neurotrophic factors after crush injury of the rat optic nerve. Systemic injection of activated T(MBP) caused an increase in the accumulation of macrophages/microglia and B cells in the injured nerve, which was greater than that seen in the injured optic nerves of untreated animals. This accumulation was accompanied by a transient, but massive, increase in the expression of neurotrophic factors. Immunocytochemical analysis demonstrated differential expression of neurotrophins by resident astrocytes and by infiltrating B cells, T cells, and macrophages. Because postinjury neuronal survival and maintenance are known to be affected by neurotrophins, our findings point to a possible contribution of a neurotrophin-related mechanism to the protective effect conferred by T cell-mediated autoimmunity on injured neurons.
The progression of degeneration in chronic optic neuropathies or in animal models of optic nerve injury is thought to be caused, at least in part, by an increase in glutamate to abnormally high concentrations. We show here that glutamate, when injected in subtoxic amounts into the vitreal body of the rat eye, transduces a self-protecting signal that renders the retinal ganglion cells resistant to further toxicity, whether glutamate-derived or not. This neuroprotective effect is attained within 24 h and lasts at least 4 days. Western blot analysis of rat retinas revealed increased amounts of bcl-2 four days after injection of glutamate in either subtoxic or toxic (120 nmol) amounts, but not after saline injection. The effects of intravitreal glutamate or saline injection on the secretion of neurotrophins by retinal ganglion cells was evaluated in rat aqueous humor 6 h, 1 day, and 4 days after injection. Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 showed similar kinetic patterns in all of the eyes; that is, they increased to a peak 1 day after the injection and returned to normal by day 4. However, increased amounts the neurotrophin receptor TrkA within the retinal ganglion cell layer and nerve fiber layer were detected 1 day after injection of glutamate in either toxic or subtoxic amounts, but not after saline injection. This finding points to the possible involvement of neurotrophin receptors in regulation of the cellular responses to glutamate challenge. Identification of the intracellular signals that trigger the glutamate-induced self-protective mechanism would shed light on the genetic balance needed for survival, and guide the development of drugs for the up-regulation of desired genes and their products.
In this study, we examined the expression of nerve growth factor (NGF) and its receptors in mouse macrophages and the mechanisms involved in the effect of NGF on tumor necrosis factor (TNF)-alpha production. Macrophages expressed NGF and the NGF receptors TrkA and p75. Treatment of J744 cells or peritoneal macrophages with NGF induced a large increase in the production of TNF-alpha. In addition, NGF induced the secretion of nitric oxide in interferon-gamma-treated J774 cells or lipopolysaccharide-treated peritoneal macrophages. The induction of TNF-alpha production by NGF was blocked by K252a, an inhibitor of the TrkA receptor. NGF induced phosphorylation and activation of extracellular signal-regulated kinase, Erk1/Erk2 and c-Jun amino-terminal kinase, whereas it did not induce phosphorylation of p38 mitogen-activated protein kinase. Inhibition of the MAP kinase-Erk kinase pathway with PD 098059 decreased the secretion of TNF-alpha by NGF. Our results suggest that NGF has an important role in the activation of macrophages during inflammatory responses via activation of mitogen-activated protein kinases.
Abstract In this study, we examined the expression of nerve growth factor (NGF) and its receptors in mouse macrophages and the mechanisms involved in the effect of NGF on tumor necrosis factor (TNF)-α production. Macrophages expressed NGF and the NGF receptors TrkA and p75. Treatment of J744 cells or peritoneal macrophages with NGF induced a large increase in the production of TNF-α. In addition, NGF induced the secretion of nitric oxide in interferon-γ-treated J774 cells or lipopolysaccharide-treated peritoneal macrophages. The induction of TNF-α production by NGF was blocked by K252a, an inhibitor of the TrkA receptor. NGF induced phosphorylation and activation of extracellular signal-regulated kinase, Erk1/Erk2 and c-Jun amino-terminal kinase, whereas it did not induce phosphorylation of p38 mitogen-activated protein kinase. Inhibition of the MAP kinase-Erk kinase pathway with PD 098059 decreased the secretion of TNF-α by NGF. Our results suggest that NGF has an important role in the activation of macrophages during inflammatory responses via activation of mitogen-activated protein kinases.
