Neuronal injury in chronic CNS inflammation.

INTRODUCTION: Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system which is characterized by inflammatory demyelination and neurodegeneration. Neurological symptoms include sensory disturbances, optic neuritis, limb weakness, ataxia, bladder dysfunction, cognitive deficits and fatigue. PATHOPHYSIOLOGY: The inflammation process with MS is promoted by several inflammatory cytokines produced by the immune cells themselves and local resident cells like activated microglia. Consecutive damaging pathways involve the transmigration of activated B lymphocytes and plasma cells, which synthesize antibodies against the myelin sheath, boost the immune attack, and result in ultimate loss of myelin. Likewise, activated macrophages and microglia are present outside the lesions in the normal-appearing CNS tissue contributing to tissue damage. In parallel to inflammatory demyelination, axonal pathology occurs in the early phase which correlates with the number of infiltrating immune cells, and critically contributes to disease severity. The spectrum of neuronal white matter and cortical damage ranges from direct cell death to subtle neurodegenerative changes such as loss of dendritic ramification and the extent of neuronal damage is regarded as a critical factor for persisting neurological deficits. Under normal conditions, CNS microglia safeguards organ integrity by constantly scanning the tissue and responding rapidly to danger signals. The main task of microglial cells is to encapsulate dangerous foci and remove apoptotic cells and debris to protect the surrounding CNS tissue; this assists with tissue regeneration in toxin-induced demyelination. In the absence of lymphocytic inflammation and in the context of non-autoimmune, pathogen-associated triggered inflammation, microglial cells protect the neuronal compartment. These mechanisms seem to be inverted in MS and other chronic neurodegenerative disorders because activated microglia and peripherally derived macrophages are shifted towards a strongly pro-inflammatory phenotype and produce the proinflammatory cytokines TNF-α and interleukin (IL)1-ß, as well as potentially neurotoxic substances including nitric oxide, oxygen radicals and proteolytic enzymes. Microglial silencing reduces clinical severity, demonstrating their active involvement in damage processes and in the immune attack against the CNS. In light of this, it is questionable whether microglia and monocyte-derived macrophages, the very last downstream effector cells in the immune reaction, actually have the capacity to influence their fate. It is more likely that the adaptive immune system orchestrates the attack against CNS cells and drives microglia and macrophages to attack oligodendrocytes and neurons. NEUROPROTECTIVE STRATEGIES: Currently, Glatiramer acetate (GA) and the interferon-ß (IFN-ß) variants are established as first-line disease modifying treatments that reduce the relapse rate, ameliorate relapse severity and delay the progression of disability in patients with relapsing-remitting MS. Similarily, sphingosine-1-phosphate (S1P) receptor agonists which influence lymphocyte migration through T cells-trapping in secondary lymphatic organs ameliorates astrogliosis and promotes remyelination by acting on S1P-receptors on astrocytes and oligodendrocytes. Ion channel blockers (e.g. sodium channel blockers), currently used for other indications, are now tested in neurodegenerative diseases to restore intracellular ion homeostasis in neurons. Axonal degeneration was significantly reduced and functional outcome was improved during treatment with Phenytoin, Flecainide and Lamotrigine. Although evidence for a direct protective effect on axons is still missing, additional immune-modulatory actions of sodium channel blockers on microglia and macrophages are likely available. In vitro-studies in axons subjected to anoxia in vitro or exposure to elevated levels of nitric oxide (NO) in vivo demonstrated the involvement of a direct effect on axons. As increased intracellular calcium levels contribute to axonal damage through activation of different enzymes such as proteases, blockade of voltage gated calcium channels is another promising target. For example, nitrendipin and bepridil ameliorate axonal loss and clinical symptoms in different models of chronic neurodegeneration. In addition to these exogenous neuroprotective patheways, endogenous neuroprotective mechanisms including neurotrophins, (re)myelination and, neurogenesis support restauration of neuronal integrity.

Divergent effects of biolistic gene transfer in a mouse model of allergic airway inflammation.

Particle-mediated epidermal delivery (PMED) of allergen genes efficiently prevents systemic sensitization and suppresses specific immunoglobulin E synthesis. We investigated in a mouse model of allergic airway disease the effect of PMED on the elicitation of local inflammatory reactions in the lung. BALB/c mice were biolistically transfected with plasmids encoding beta-galactosidase (betaGal) as model allergen under control of the DC-targeting fascin promoter and the ubiquitously active cytomegalovirus promoter, respectively. Mice were challenged intranasally with betaGal-protein with or without intermediate sensitization with betaGal adsorbed to aluminiumhydroxide. Subsequently, local cytokine production and recruitment of IFN-gamma-producing CD8(+) effector T cells into the airways were determined, and inflammatory parameters such as cellular infiltration in the bronchoalveolar lavage (BAL) and airway hyperresponsiveness (AHR) were measured. PMED of betaGal-encoding plasmids before sensitization significantly reduced frequencies of eosinophils in the BAL and shifted the local T helper (Th) cell response from a distinct Th2 response toward a Th1-biased response. However, AHR triggered by allergen challenge via the airways was not alleviated in vaccinated mice. Most important, we show that PMED using betaGal-encoding DNA without subsequent sensitization recruited Tc1 cells into the lung and caused a Th1-prone local immune response after subsequent intranasal provocation, accompanied by neutrophilic infiltration into the airways and elicitation of AHR. We conclude that robust Th1/Tc1 immune responses, although highly effective in the counter-regulation of local Th2-mediated pathology, might as well trigger local inflammatory reactions in the lung and provoke the induction of AHR in the mouse model of allergic airway disease.