Inflammation occurs rapidly in response to acute brain insults such as stroke, haemorrhage or trauma, and can be sustained for long periods of time, for example in Alzheimer's or Parkinson's diseases and multiple sclerosis. Experimental evidence indicates that inflammation plays a major role in neurodegeneration under these conditions, and that the cytokine IL-1 (interleukin-1) is a pivotal mediator. IL-1 is expressed rapidly in response to neuronal injury, predominantly by microglia, and elevated levels of endogenous or exogenous IL-1 markedly exacerbate injury. The naturally occurring IL-1RA (IL-1 receptor antagonist) markedly inhibits ischaemic, excitotoxic and traumatic brain injury in rodents, and has shown promise in a Phase II clinical trial in stroke patients. The mechanisms of IL-1 expression, release and action in neurodegeneration are not fully elucidated and appear multiple. Systemic IL-1 markedly enhances ischaemic brain injury via release of neutrophils into circulation, neutrophil adhesion to injured cerebrovasculature and CNS (central nervous system) invasion, and cell death via activation of matrix metalloproteinase-9. IL-1 also influences the release of toxins from glial and endothelial cells. Neuronal responses to excitotoxins and physiological factors may have an impact on neuronal survival. IL-1RA, delivered peripherally, can enter the CNS in animals and humans and has no adverse effects in stroke or subarachnoid haemorrhage patients, but shows potential benefit in acute stroke patients.

The TNF/TNFR system exerts multiple proinflammatory and immunosuppressive functions in the pathogenesis of chronic inflammation and autoimmunity. In EAE, the experimental model of Multiple Sclerosis (MS), genetic ablation of TNFR2, results in exacerbated immune reactivity and chronic disease course. The underlying mechanism driving this immunosuppressive function of TNFR2 remains unclear. We show here that chronic exacerbated EAE in TNFR2 KO mice is associated with increased Th17-cell responses and reduced numbers of Foxp3 1 Treg cells both in the spinal cord and peripheral lymphoid organs. Treg cells from TNFR2-deficient animals developing EAE show decreased proliferative and suppressive functions, both ex vivo and in vivo, and appear responsible for the exacerbated non-remitting disease, as evidenced by phenotypic rescue following adoptive transfer of Treg cells from WT but not TNFR2 À/À donors. Reciprocal BM transplantation experiments between WT and TNFR2-deficient mice demonstrated that the capacity of TNFR2 to support Treg-cell expansion and function during EAE is non-intrinsic to Treg or other haematopoietic cells but requires expression of TNFR2 in radiation-resistant cells of the host. These results reveal a previously unsuspected role for non-haematopoietic TNFR2 in modulating Treg-cell expansion and immune suppression during development of autoimmunity and suggest that a similar mechanism may affect chronicity and relapses characterizing human autoimmune disease, including MS.Key words: Animal models . Autoimmunity . Cellular immunology . Multiple sclerosis . TNFRZ Supporting Information available online IntroductionMultiple sclerosis (MS) is a chronic neuroimmunological disease characterized by disseminated foci of inflammatory demyelination in the brain and spinal cord (SC), commonly affecting young adults between the age of 20 and 40. Typically, MS has a relapsing and remitting course followed by the development of irreversible neurological disability due to persistent axonal dysfunction and neuronal loss. CNS demyelination, the pathological hallmark of MS is brought about by autoreactive à These authors contributed equally to this work. , which produces T-cell-driven demyelination with components from cellular and humoral immunity leading to axonal injury associated with disability ranging from mild weakness to severe paralysis [3,4]. Dysfunctional immune suppressive/tolerogenic mechanisms causing aggressive autoimmune behavior and demyelination are thought to play a dominant pathogenic role both in EAE and MS [1,3]. Chronicity and relapses in autoimmune diseases including MS seem to involve defective integration of inflammatory and antiinflammatory cues. Numerous studies have dissected the multiple and opposing roles of cytokine-producing cells in the autoimmune pathogenesis of MS and EAE. IL-17-(Th17) [5,6] and IFN-g-(Th1) [7][8][9][10] producing cells are considered the effector T (Teff) cells that have been detected in SC lesions at different stages of the disease progression and are thought t...

TPL-2 expression is required for efficient polarization of naïve T cells to Th1 effector cells in vitro, and for Th1-mediated immune responses. In the present study, we investigated the potential role of TPL-2 in Th17 cells. TPL-2 was found to be dispensable for Th17 cell differentiation in vitro, and for the initial priming of Th17 cells in experimental autoimmune encephalomyelitis (EAE), a Th17 cell-mediated disease model for multiple sclerosis. Nevertheless, TPL-2-deficient mice were protected from EAE, which correlated with reduced immune cell infiltration, demyelination and axonal damage in the CNS. Adoptive transfer experiments demonstrated that there was no T cell-intrinsic function for TPL-2 in EAE, and that TPL-2 signaling was not required in radiation-sensitive hematopoietic cells. Rather, TPL-2 signaling in radiation-resistant stromal cells promoted the effector phase of the disease. Importantly, using a newly generated mouse strain expressing a kinase-inactive form of TPL-2, we demonstrated that stimulation of EAE was dependent on TPL-2’s catalytic activity, and not its adaptor function to stabilize the associated ubiquitin-binding protein ABIN-2. Our data therefore raise the possibility that small molecule inhibitors of TPL-2 may be beneficial in multiple sclerosis therapy.

Background and purpose: Interleukin (IL)-1 is a key mediator of inflammatory and host defence responses and its effects in the brain are mediated primarily via effects on glia. IL-1 induces release of inflammatory mediators such as IL-6 from glia via the type-1 receptor (IL-1R1) and established signalling mechanisms including mitogen-activated protein kinases and nuclear factor kappa-B. IL-1 also modifies physiological functions via actions on neurones, through activation of the neutral sphingomyelinase (nSMase)/Src kinase signalling pathway, although the mechanism of IL-1-induced IL-6 synthesis in neurones remains unknown. Experimental approach: Primary mouse neuronal cell cultures, ELISA, Western blot and immunocytochemistry techniques were used. Key results: We show here that IL-1b induces the synthesis of IL-6 in primary mouse neuronal cultures, and this is dependent on the activation of IL-1R1, nSMase and Src kinase. We demonstrate that IL-1b-induced Src kinase activation triggers the phosphorylation of the NMDA receptor NR2B subunit, leading to activation of Ca 2 þ /calmodulin-dependent protein kinase II (CamKII) and the nuclear transcription factor CREB. We also show that NR2B, CamKII and CREB are essential signalling elements involved in IL-1b-induced IL-6 synthesis in neurones. Conclusions and implications:These results demonstrate that IL-1 interacts with the same receptors on neurones and glia to elicit IL-6 release, but does so via distinct signalling pathways. The mechanism by which IL-1b induces IL-6 synthesis in neurones could be critical in both physiological and pathophysiological actions of IL-1b, and may provide a new therapeutic target for the treatment of acute CNS injury.

Interleukin (IL)-1 is a key mediator of neuroinflammation via actions of two agonists IL-1alpha and beta that bind to the IL-1 type I receptor (IL-1RI), and are thought to trigger identical responses. However, evidence suggests that IL-1alpha and beta may have differential actions in the central nervous system (CNS). The objective of this study was to test the hypothesis that IL-1alpha and beta differentially regulate the expression of IL-6 and chemokines KC, IP-10 and MCP-1 in primary neurones. Here we demonstrate that, whilst IL-1beta induced significant synthesis of IL-6 in neurones, IL-1alpha had no effect. In contrast, IL-1alpha and beta induced strong synthesis and constitutive release of chemokines KC, IP-10 and MCP-1 from neurones, and these responses were IL-1RI-dependent. Whilst IL-1beta-induced IL-6 synthesis was dependent on the nSMase/Src kinase signalling cascade, specific inhibitors of nSMase (3-OMS) and Src kinase (PP2) failed to inhibit IL-1alpha- and IL-1beta-induced chemokines synthesis, suggesting the existence of alternative signalling pathway(s) in neurones.

No abstract

Neural progenitor cells in the developing retina extend processes that stretch from the basal vitread surface to the apical ventricular surface. During the cell cycle, the nucleus undergoes interkinetic nuclear migration (INM), moving in a vitread direction during G1, passing through S-phase at its peak and then, on entering G2, returning towards the ventricular surface where it enters M-phase and divides. We have previously shown that individual saltatory movements of the nucleus correlate with transient changes in cytosolic calcium concentration within these progenitor cells and that these events spread to neighbouring progenitors through connexin43 (Cx43) gap junction channels, thereby coordinating the migration of coupled clusters of cells. Disrupting coupling with pharmacological agents, Cx43-specific antisense oligodeoxynucleotides (asODNs) or dominant negative Cx43 (dnCx43) inhibits the sharing of calcium events, reducing the number that each cell experiences and significantly slowing INM. We have developed protocols for imaging migrating progenitor cells by confocal microscopy over relatively short periods, and by multiphoton microscopy over more extended periods that include complete cell cycles. We find that perturbing gap junctional communication not only slows the INM of progenitor cells but also apparently prevents them from changing direction at critical phases of the cell cycle. It also disrupts the migration of young neurons to their appropriate layers after terminal division and leads to their ectopic differentiation. The ability to perform extended time-lapse imaging over 3D volumes in living retina using multiphoton microscopy should now allow fundamental mechanisms governing development of the retinal neuroepithelium to be probed in detail.

The cover is based on a spinal cord histology section taken from a TNFR2−/− mouse adoptively transferred with TNFR2−/− Treg cells prior to immunization with MOG35–55 to induce EAE. The section is stained with Luxol Fast blue to detect demyelination; Luxol Fast Red, which detects inflammatory infiltration, is the counterstain. The image is taken from the article by Tsakiri et al. (pp. 403–412) in which it is shown that TNFR2 on non‐haematopoietic cells is necessary for Treg‐cell suppressive activity and repression of EAE development. The colour of the image has been digitally altered for the cover.