Iron and the immune system.

Iron and immunity are closely linked: firstly by the fact that many of the genes/proteins involved in iron homoeostasis play a vital role in controlling iron fluxes such that bacteria are prevented from utilising iron for growth; secondly, cells of the innate immune system, monocytes, macrophages, microglia and lymphocytes, are able to combat bacterial insults by carefully controlling their iron fluxes, which are mediated by hepcidin and ferroportin. In addition, lymphocytes play an important role in adaptive immunity. Thirdly, a variety of effector molecules, e.

Attenuation of proliferation in oligodendrocyte precursor cells by activated microglia.

Activated microglia can influence the survival of neural cells through the release of cytotoxic factors. Here, we investigated the interaction between Toll-like receptor 4 (TLR4)-activated microglia and oligodendrocytes or their precursor cells (OPC). Primary rat or N9 microglial cells were activated by exposure to TLR4-specifc lipopolysaccharide (LPS), resulting in mitogen-activated protein kinase activation, increased CD68 and inducible nitric oxide synthase expression, and release of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6).

Stem cells are resistant to TRAIL receptor-mediated apoptosis.

New therapeutic approaches aim to eradicate tumours by expression of tumouricidal proteins in the tumour stroma. One such anti-neoplastic protein is tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) because it induces apoptosis in cancerous cells, but not in non-transformed cells. Stem cells can migrate to, survive and proliferate in tumours.

Differentiation of human fetal mesenchymal stem cells into cells with an oligodendrocyte phenotype.

The potential of mesenchymal stem cells (MSC) to differentiate into neural lineages has raised the possibility of autologous cell transplantation as a therapy for neurodegenerative diseases. We have identified a population of circulating human fetal mesenchymal stem cells (hfMSC) that are highly proliferative and can readily differentiate into mesodermal lineages such as bone, cartilage, fat and muscle. Here, we demonstrate for the first time that primary hfMSC can differentiate into cells with an oligodendrocyte phenotype both in vitro and in vivo.

Consequential apoptosis in the cerebellum following injury to the developing rat forebrain.

In focal brain lesions, alterations in blood flow and cerebral metabolism can be detected in brain areas remote from the primary injury. The cellular consequences of this phenomenon, originally termed diaschisis, are not fully understood. Here, we report that in two distinct models of forebrain injury, neuronal death in the cerebellum, a site distant to the primary injury, results as consequence of neuronal loss in the forebrain.

Stimulation of microglial metabotropic glutamate receptor mGlu2 triggers tumor necrosis factor alpha-induced neurotoxicity in concert with microglial-derived Fas ligand.

Activated microglia may be detrimental to neuronal survival in a number of neurodegenerative diseases. Thus, strategies that reduce microglial neurotoxicity may have therapeutic benefit. Stimulation of group II metabotropic glutamate (mGlu) receptors on rat primary microglia with the specific group II agonist 2S,2'R,3'R-2-(2',3'-dicarboxy-cyclopropyl)glycine for 24 h induced microglial activation and resulted in a neurotoxic microglial phenotype.

Pure albumin is a potent trigger of calcium signalling and proliferation in microglia but not macrophages or astrocytes.

Microglial activation is implicated in the neurotoxicity of neurodegenerative diseases. Raised intracerebral levels of albumin are associated with the pathology of Alzheimer's disease, multiple sclerosis, and stroke where blood-brain barrier damage is evident. We report here that treatment of primary cultured microglia and the N9 microglial cell line with pure albumin, or albumin in which fatty acids and immunoglobulins remain attached (fraction V), induced a rise in intracellular calcium.

Microglia release activators of neuronal proliferation mediated by activation of mitogen-activated protein kinase, phosphatidylinositol-3-kinase/Akt and delta-Notch signalling cascades.

Microglia, the resident macrophage of the brain, can release substances that aid neuronal development, differentiation and survival. We have investigated the effects of non-activated microglia on the survival of cultured rat cerebellar granule neurones. Microglial-conditioned medium, collected from primary rat microglial cultures, was used to treat 7-day-in-vitro neurones, and neuronal viability and proliferation was assessed following a further 1 or 7 days in culture.

Activation of microglial group III metabotropic glutamate receptors protects neurons against microglial neurotoxicity.

A reduction in microglial activation and subsequent neurotoxicity may prove critical for neuroprotection in neurodegenerative diseases. We examined the expression and functionality of group III metabotropic glutamate (mGlu) receptors on microglia. Rat microglia express mRNA and receptor protein for group III mGlu receptors mGlu4, mGlu6, and mGlu8 but not mGlu7.

A role for caspase-1 and -3 in the pathology of experimental allergic encephalomyelitis : inflammation versus degeneration.

Axonal loss, already present in the acute and first relapse phases of experimental allergic encephalomyelitis (EAE) in the ABH mouse, only becomes apparent in the third relapse in the interleukin-12 model of relapsing EAE in the Lewis rat. Caspase-1 immunostaining in the spinal cord of Lewis rats was mainly localized to inflammatory cuffs with the greatest proportion of active caspase-1-positive cells detected during the first and second relapses, correlating with enzyme activity and protein on Western blots. However, in the spinal cord of ABH mice during acute EAE, caspase-1 immunostaining was localized both on inflammatory and neuronal cells, again correlating with enzyme activity and protein production.

Improved neuroprotection with hypothermia delayed by 6 hours following cerebral hypoxia-ischemia in the 14-day-old rat.

Since hypothermia may be a potential treatment for perinatal cerebral hypoxic-ischemic injury, we used an established neonatal model of hypoxia-ischemia to determine the time after injury at which cooling had the best protective effect. Fourteen-day-old Wistar rats were subjected to right carotid artery ligation and hypoxia (8% O(2) for 90 min). Immediately at the end of hypoxia (defined as 0h), animals were either maintained at normal body temperature until sacrifice (normothermia) or subjected to hypothermia.