Apart from potential roles in anti-tumor surveillance, the TNF-related apoptosis-inducing ligand (TRAIL) has important regulatory functions in the host immune response. We studied antiinflammatory effects of endogenous and recombinant TRAIL (rTRAIL) in experimental meningitis. Following intrathecal application of pneumococcal cell wall, a TLR2 ligand, we found prolonged inflammation, augmented clinical impairment, and increased apoptosis in the hippocampus of TRAIL -/-mice. Administration of rTRAIL into the subarachnoid space of TRAIL -/-mice or reconstitution of hematopoiesis with wild-type bone marrow cells reversed these effects, suggesting an autoregulatory role of TRAIL within the infiltrating leukocyte population. Importantly, intrathecal application of rTRAIL in wild-type mice with meningitis also decreased inflammation and apoptosis. Moreover, patients suffering from bacterial meningitis showed increased intrathecal synthesis of TRAIL.Our findings provide what we believe is the first evidence that TRAIL may act as a negative regulator of acute CNS inflammation. The ability of TRAIL to modify inflammatory responses and to reduce neuronal cell death in meningitis suggests that it may be used as a novel antiinflammatory agent in invasive infections.

Reactive oxygen and nitrogen species are released by immune-competent cells and contribute to cellular damage. On the other hand, certain pathogens, including Streptococcus pneumoniae, are known to produce hydrogen peroxide (H 2 O 2 ), while production of nitrogen radicals by bacteria presumably occurs but has been poorly studied. We determined the relative contributions of bacterial versus host-derived oxygen and nitrogen radicals to cellular damage in pneumococcal infection. A special focus was placed on peroxynitrite as a hypothetical common product formed by the reaction of H 2 O 2 and NO. In microglial cultures, reduction of the formation of 3-nitrotyrosine and cellular damage required H 2 O 2 -deficient (⌬spxB or ⌬carB) pneumococci and inhibition of host NO synthesis with aminoguanidine. In infected C57BL/6 mice, neuronal loss and immunopositivity for nitrotyrosine in the dentate gyrus were markedly reduced with ⌬spxB or ⌬carB bacterial mutants and in inducible nitric oxide synthase knockout mice. We conclude that although host and bacteria both produce oxygen and nitrogen radicals, the interplay of prokaryotic H 2 O 2 and eukaryotic NO is a major contributor to cellular damage in pneumococcal meningitis.The host response to invading bacteria involves not only immune responses but also release of nonspecific and chemically highly reactive molecules. Reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI) can damage membrane structures and DNA of prokaryotic as well as eukaryotic cells. Considerable quantities of ROI are produced by macrophages and polymorphonuclear leukocytes in response to different bacterial stimuli. Additionally, macrophages are significant sources of RNI such as nitric oxide (NO). As a joint product of ROI and RNI, peroxynitrite is a particularly destructive molecule that exerts antimicrobial effects but also initiates host cell damage (6, 7).Reactive oxygen species (ROS) are generated by oxidative metabolism of all aerobic cells, but particularly efficient production is achieved by the NADPH (phagocyte) oxidase of neutrophilic and eosinophilic granulocytes and mononuclear phagocytes (3). This enzyme complex produces superoxide (O 2 Ϫ ) from oxygen, most of which is then converted by superoxide dismutase (SOD) to hydrogen peroxide (H 2 O 2 ) (22). Further reduction yields hydroxyl radicals (OH) and ultimately H 2 O. In the host, NO is generated by a family of NO synthases (1). Of these enzymes, the calcium-dependent neuronal and endothelial isoforms are constitutively active and produce nanomolar amounts of NO as a strictly local neurotransmitter and modulator of vascular tone. Conversely, a calcium-independent, inducible isoform (inducible nitric oxide synthase [iNOS]) is inactive in most resting cells and is induced in cells with phagocytic capacities under pathological conditions, e.g., in infection, trauma, or ischemia (11).While the production of ROS and RNI in the host has been extensively studied, it is less well appreciated that bacteria also produce these...

Bacterial meningitis is a major infectious cause of neuronal degeneration in the hippocampus. Neurogenesis, a continuous process in the adult hippocampus, could ameliorate such loss. Yet the high rate of sequelae from meningitis suggests that this repair mechanism is inefficient. Here we used a mouse model of nonreplicative bacterial meningitis to determine the impact of transient intracranial inflammation on adult neurogenesis. Experimental meningitis resulted in a net loss of neurons, diminished volume, and impaired neurogenesis in the dentate gyrus for weeks following recovery from the insult. Inducible nitric oxide synthase (iNOS) immunoreactivity was prominent in microglia in nonproliferating areas of the dentate gyrus and hilus region after meningitis induction. Treatment with the specific iNOS inhibitor N6-(1-iminoethyl)-L-lysine restored neurogenesis in experimental meningitis. These data suggest that local central nervous system inflammation in and of itself suppresses adult neurogenesis by affecting both proliferation and neuronal differentiation. Repair of cognitive dysfunction following meningitis could be improved by intervention to interrupt these actively suppressive effects.