Meningitis and meningoencephalitis caused by Escherichia coli are associated with high rates of mortality. When an infection occurs, Toll-like receptors (TLRs) expressed by microglial cells can ...recognize pathogen-associated molecular patterns and activate multiple steps in the inflammatory response that coordinate the brain's local defense, such as phagocytosis of invading pathogens. An upregulation of the phagocytic ability of reactive microglia could improve the host defense in immunocompromised patients against pathogens such as E. coli. Here, murine microglial cultures were stimulated with the TLR agonists Pam₃CSK₄ (TLR1/TLR2), lipopolysaccharide (TLR4), and CpG oligodeoxynucleotide (TLR9) for 24 h. Upon stimulation, levels of tumor necrosis factor alpha and the neutrophil chemoattractant CXCL1 were increased, indicating microglial activation. Phagocytic activity was studied after adding either E. coli DH5α or E. coli K1 strains. After 60 and 90 min of bacterial exposure, the number of ingested bacteria was significantly higher in cells prestimulated with TLR agonists than in unstimulated controls (P < 0.01). Addition of cytochalasin D, an inhibitor of actin polymerization, blocked >90% of phagocytosis. We also analyzed the ability of microglia to kill the ingested E. coli strains. Intracellularly surviving bacteria were quantified at different time points (90, 150, 240, and 360 min) after 90 min of phagocytosis. The number of bacteria killed intracellularly after 6 h was higher in cells primed with the different TLR agonists than in unstimulated microglia. Our data suggest that microglial stimulation by the TLR system can increase bacterial phagocytosis and killing. This approach could improve central nervous system resistance to infections in immunocompromised patients.
Multiple sclerosis (MS) is a complex inflammatory disease of the central nervous system (CNS) with an unknown etiology. Thereby, MS is not a uniform disease but rather represents a spectrum of ...disorders, where each aspect needs to be modeled with specific requirements-for a systematic overview see our previous issue of this review (Kurschus, Wortge, & Waisman, 2011). However, there is broad consensus about the critical involvement of the immune system in the disease pathogenesis. To better understand how the immune system contributes to CNS autoimmunity, the model of experimental autoimmune encephalomyelitis (EAE) was developed. EAE can be induced in susceptible animals in many different ways, with the most popular protocol involving the activation of self-reactive T cells by a peptide based on the myelin oligodendrocyte glycoprotein sequence. In the last 10 years this model has led to major advances in our understanding of the immune system, especially the nature of IL-17-producing T cells (Th17 cells), host-microbiome interactions, the gut-brain axis and how the immune system can cause damage in different regions of the brain and the spinal cord. This update summarizes some of the main achievements in the field in the last 10 years.
The essential amino acid tryptophan (Trp) is metabolized by gut commensals, yielding in compounds that affect innate immune cell functions directly, but also acting on the aryl hydrocarbon receptor ...(AHR), thus regulating the maintenance of group 3 innate lymphoid cells (ILCs), promoting T helper 17 (T
H
17) cell differentiation, and interleukin-22 production. In addition, microbiota-derived Trp metabolites have direct effects on the vascular endothelium, thus influencing the development of vascular inflammatory phenotypes. Indoxyl sulfate was demonstrated to promote vascular inflammation, whereas indole-3-propionic acid and indole-3-aldehyde had protective roles. Furthermore, there is increasing evidence for a contributory role of microbiota-derived indole-derivatives in blood pressure regulation and hypertension. Interestingly, there are indications for a role of the kynurenine pathway in atherosclerotic lesion development. Here, we provide an overview on the emerging role of gut commensals in the modulation of Trp metabolism and its influence in cardiovascular disease development.
The cellular sources of interleukin 6 (IL-6) that are relevant for differentiation of the T
17 subset of helper T cells remain unclear. Here we used a novel strategy for the conditional deletion of ...distinct IL-6-producing cell types to show that dendritic cells (DCs) positive for the signaling regulator Sirpα were essential for the generation of pathogenic T
17 cells. Using their IL-6 receptor α-chain (IL-6Rα), Sirpα
DCs trans-presented IL-6 to T cells during the process of cognate interaction. While ambient IL-6 was sufficient to suppress the induction of expression of the transcription factor Foxp3 in T cells, trans-presentation of IL-6 by DC-bound IL-6Rα (called 'IL-6 cluster signaling' here) was needed to prevent premature induction of interferon-γ (IFN-γ) expression in T cells and to generate pathogenic T
17 cells in vivo. Our findings should guide therapeutic approaches for the treatment of T
17-cell-mediated autoimmune diseases.
Pro-inflammatory T cells in the central nervous system (CNS) are causally associated with multiple demyelinating and neurodegenerative diseases
, but the pathways that control these responses remain ...unclear. Here we define a population of inflammatory group 3 innate lymphoid cells (ILC3s) that infiltrate the CNS in a mouse model of multiple sclerosis. These ILC3s are derived from the circulation, localize in proximity to infiltrating T cells in the CNS, function as antigen-presenting cells that restimulate myelin-specific T cells, and are increased in individuals with multiple sclerosis. Notably, antigen presentation by inflammatory ILC3s is required to promote T cell responses in the CNS and the development of multiple-sclerosis-like disease in mouse models. By contrast, conventional and tissue-resident ILC3s in the periphery do not appear to contribute to disease induction, but instead limit autoimmune T cell responses and prevent multiple-sclerosis-like disease when experimentally targeted to present myelin antigen. Collectively, our data define a population of inflammatory ILC3s that is essential for directly promoting T-cell-dependent neuroinflammation in the CNS and reveal the potential of harnessing peripheral tissue-resident ILC3s for the prevention of autoimmune disease.
Abstract
Pro-inflammatory T cells in the central nervous system (CNS) are causally associated with multiple demyelinating and neurodegenerative diseases, but the pathways controlling these responses ...remain unclear. Here we define a population of group 3 innate lymphoid cells (ILC3s) that are uniquely enriched in the CNS during a mouse model of multiple sclerosis. CNS-associated ILC3s exhibit distinct transcriptional profiles, localize in proximity to infiltrating T cells, and express major histocompatibility complex class II (MHCII) and co-stimulatory molecules. Critically, antigen presentation by ILC3s was required to selectively promote pro-inflammatory T cell responses in the CNS and the development of multiple sclerosis-like disease. In contrast, antigen presenting ILC3s in the periphery lack co-stimulatory molecules and did not appear to contribute to disease induction, but rather could induce tolerance in autoimmune T cells and prevent multiple sclerosis-like disease when experimentally targeted to present myelin antigen. Collectively, our data demonstrate an essential role for CNS-associated ILC3s in promoting T cell-dependent neuroinflammation and reveal the potential to harness peripheral ILC3s for the prevention of autoimmune disease.
The notion of "immune privilege" of the brain has been revised to accommodate its infiltration, at steady state, by immune cells that participate in normal neurophysiology. However, the immune ...mechanisms that regulate learning and memory remain poorly understood. Here, we show that noninflammatory interleukin-17 (IL-17) derived from a previously unknown fetal-derived meningeal-resident γδ T cell subset promotes cognition. When tested in classical spatial learning paradigms, mice lacking γδ T cells or IL-17 displayed deficient short-term memory while retaining long-term memory. The plasticity of glutamatergic synapses was reduced in the absence of IL-17, resulting in impaired long-term potentiation in the hippocampus. Conversely, IL-17 enhanced glial cell production of brain-derived neurotropic factor, whose exogenous provision rescued the synaptic and behavioral phenotypes of IL-17-deficient animals. Together, our work provides previously unknown clues on the mechanisms that regulate short-term versus long-term memory and on the evolutionary and functional link between the immune and nervous systems.
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