Meeting Report: Neuroinflammation in neuronal degeneration and repair
Parghelia (VV) Italy, 13-16 September 2006

In the opening lecture, Stuart Lipton (La Jolla, USA) presented an overview on the role of inflammatory mediators such as nitric oxide (NO) and reactive oxygen species (ROS) in neurodegenerative diseases, and more recent data on post-translational modifications, such as S-nitrosylation, which can contribute to protein misfolding and the progression of neurodegenerative diseases. The first part of the talk focussed on recent data on the protein-disulfide isomerase (PDI), an enzyme responsible for normal protein folding in the endoplasmic reticulum. S-nitrosylation of PDI (SNO-PDI) inhibits its enzymatic activity, leads to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response which contributes to neuronal cell injury and loss. Interestingly, SNO-PDI formation occurs in several human diseases, including AD and PD.

The first session of the meeting focussed on the basic mechanisms of neuroinflammation. The talks were addressed to the understanding of the general principles of innate immunity and inflammation in the brain and of the main cellular and molecular players involved in these processes. Philipe Gasque (Cardiff, UK and La Reunion, France) reviewed the main members of the increasing list of “eat me “ and “not eat me” signals which may be expressed by neurons in the brain together with their interacting partners on “professional” or “amateur” macrophages. In particular, a new family of receptors (CD93, CD141 and CD248) seem to have a relevant role in controlling the local innate immune response. An intriguing possibility raised by Gasque is that of “re-educating” and stimulating the resident phagocytes to promote clearance of pathogens (e.g. Prion), toxic cell debris (e.g. amyloid fibrils and myelin) and apoptotic/necrotic cells. b>Giovanbattista Bonanno (Genoa, Italy) illustrated the preparation of gliosomes, subcellular re-sealed particles from glial cells, and their use as an easily accessible in vitro system for assessing glial cells response to several stimuli. In this system, the multifunctional protein HMGB1 (High Mobility Group Box 1) was shown to induce Ca2+-dependent neurotransmitter release possibly via its interaction with RAGE (Receptor for Advanced Glycation End Products). On the same protein focussed also Alberto Chiarugi’s (Florenz, Italy) talk. This protein was originally identified as a DNA-binding protein and a transcriptional regulator and it has been recently shown to act as a potent pro-inflammatory cytokine-like factor. While in apoptotic cells HMGB1 maintains its nuclear localisation, in necrotic cells it is released into the extracellular space. Here the protein acts on several targets on immune cells (RAGE, TLR-2 and -4 receptors) activating an auto-amplifying inflammatory signalling cascade. In vitro and in vivo data seem to support an active role of HMGB1 during ischemia in the brain.

Andrea Volterra (Lausanne, Switzerland and Milan, Italy) discussed the current vision on astrocytes as an active component of the central nervous system and not mere passive supporting cells. Calcium-dependent glutamate release by astrocytes can be triggered by various stimuli, including the pro-inflammatory cytokine tumour necrosis factor a (TNFa), acting via prostaglandins. While this is usually part of a physiological interplay between neurons and astrocytes, in models of acute inflammation the TNFa-dependent glutamate release by glia can become an important component of the degenerative process. Still on astrocytes, Milos Pekny (Goteborg, Sweden) discussed the role of these cells and the complement system in neuronal plasticity and the recent evidence that products from complement activation promote both basal and ischemia-induced neurogenesis in the adult CNS. In the first part of his talk, particular emphasis was given to the data from mouse genetic models in which the absence of different intermediate filament proteins in astrocytes (e.g. GFAP-/-, Vim-/-, GFAP-/-Vim-/-) lead to attenuation of reactive gliosis with distinct pathophysiological and clinical consequences. The same mice subjected to several trauma models have also contributed to the understanding of the role of IF upregulation and reactive astrocytes in CNS trauma.

Matrix metalloproteinases were then taken into the picture by two presentations. A detailed and comprehensive overview was given by Anthony Turner (Leeds, UK) on the different roles metalloproteinases can play in neurodegeneration and neuroprotection. Emphasis was given to metallopeptidases involved in the metabolism of the neurotoxic amyloid peptide (A?) such as neprilysins (NEP), insulin-degrading enzyme (IDE), angiotensin-converting enzyme and, plasmin and the numerous factors (genetic, environmental, age) and conditions (e.g. hypoxia and ischemia) influencing the activity of these proteases were discussed. Data on a possible new role of matrix metalloproteinases (MMP) in brain ischemia were presented by Diana Amantea (Cosenza, Italy). MMP-2 and MMP-9 expression and activity increase during brain ischemia following middle cerebral artery occlusion. MMPs inhibitors, which prevent this increase, also reduce the infarct area and the processing of neuroinflammatory mediators such as IL-1beta.

Inflammatory and immune mechanisms in the periphery and the central nervous system play an important role also in chronic pain. Stephen Hunt highlighted the role of some of these inflammatory mediators in the progression of different pain models. In particular, the talk focussed on the role of tumour necrosis factor in macrophage recruitment during arthritis, the importance of nerve growth factor in maintaining pain in bone cancer and the role of dorsal horn microglial cells in neuropathic pain states.

Barbara Viviani (Milan, Italy) extended her previous findings to neurons exposed to the HIV-envelope glycoprotein gp120. Using a sandwich co-culture of primary hippocampal neurons and glia, she showed that IL-1beta released from glia by gp120 drives neural death through tyrosine phosphorylation and trafficking of NMDA receptors.

Richard Ransohoff (Cleveland, USA) overviewed the complex world of chemokines and their receptors and discussed how the paradigm on this family of peptides has changed over the past few years. This large family of structurally similar proteins is crucial in the development and deployment of leukocytes. They act as mediators of cellular migration in embryogenesis (including CNS pattering during development), of leukocyte migration in immune surveillance, and of effector responses in lymphoid and non-lymphoid tissues. The picture is complicated by the fact that virtually all types of cells have the potential to secrete chemokines, although in different amounts and combinations. Recently, it has become clear that constitutive chemokines in the CNS support developmental and neurophysiological functions as well as regulating the activation of microglia and together with their receptors may play a key role in physiological but also in pathological conditions. This makes them potential attractive drug targets for the regulation of inflammation and immunity.

Diego Centonze (Rome, Italy) presented work from electrophysiological studies on corticostriatal brain slices from mice with experimental autoimmune encephalomyelitis, a preclinical model of multiple sclerosis. In this system, striatal neurons show major alterations in both excitatory and inhibitory neurotransmission with increased glutamatergic transmission and decreased GABAergic function. The results point towards the occurrence of important processes of synaptic dysfunction during the early phases of the disease.

Tony Wyss-Coray (Stanford, USA) reviewed the evidence that identify immune and inflammatory pathways as potential modulators of Alzheimer’s disease. Although there are still no convincing genetic or other data to support an early role of inflammation in Alzheimer’s disease, sophisticated mouse models with genetic manipulations of inflammatory pathways indicate that inflammatory processes may be a driving force of pathology. On the other hand, a growing number of animal studies support also the idea that some inflammatory responses are beneficial and may be effective in preventing or treating the disease. Thus, although research on the role of neuroinflammatory mechanisms in the onset and/or progression of neurodegenerative disease started in the context of Alzheimer’s disease, we are still far from having a conclusive picture. Joe Rogers (Sun City, USA) analysed further the state of the knowledge on the role of neuroinflammation in Alzheimer’s disease. He then discussed the main findings on neuroinflammatory mechanisms in the more recent context of Parkinson’s disease commenting on commonalities and differences in the two conditions. Roger’s data point towards A? deposition stimulating inflammatory responses and neurons being a non-selective, bystander target in Alzheimer’s disease, whereas dopamine itself may stimulate activated microglia to attack dopaminergic neurons and therefore neurons being a direct, selective target in Parkinson’s disease. In the context of Parkinson’s disease, Howard Gendelman (Omaha, USA) reported on the “protective and destructive role” of T linfocytes and presented data on synuclein-linked neuroimmunity in PD models. Based on studies showing that innate immunity, especially glial inflammatory factors (proinflammatory cytokines, reactive oxygen and nitrogen species), contribute to the degeneration of the nigrostriatal dopaminergic pathway and on the notion that T lymphocytes present in brain tissue may affect disease progression, Gendelman’s and collaborators tested the hypothesis that immunization strategies could induce T cells to enter inflamed nigrostriatal tissue, attenuate innate glial immunity, and increase local neurotrophic factor production with neuroprotective effect. The immunization strategy with random amino acid polymer copolymer-1 (Cop-1) resulted in significant protection of nigrostriatal neurons in MPTP-induced neurodegeneration and the effect was abrogated by depletion of donor T cells.

Luisa Minghetti (Rome, Italy) reviewed the role of microglia activation and inflammatory responses in prion disease. Her talk focussed on cyclooxygenase -2 (COX-2), a major player in inflammatory reactions in peripheral tissues as well as in the brain. Data from animal models showed increased hippocampal levels of PGE2 and a strong induction of COX-2 expression in microglia associated with the progression of disease. Elevated levels of PGE2 in the cerebro-spinal fluid of patients affected by genetic or sporadic CJD support the animal studies.

Linda Van Eldik (Chicago, USA) illustrated the process of drug research and development in general, and a novel integrative drug discovery approach to identify new compounds targeted to modulate glia proinflammatory cytokine up-regulation. The development of therapeutics that suppress neuroinflammatory responses of activated glia, such as elevations in proinflammatory cytokines, would have broad impact across diverse neurological disease indications. The novel compound presented, Minozac, appears to have this feature.


Financial Report

Giacinto Bagetta
Department of Pharmacobiology, University of Calabria, 87036 Arcavacata di Rende (Cosenza, Italy)