Pathogen-derived Stimuli Research Articles

Platelet Behavior Contributes to Neuropathologies: A Focus on Alzheimer's and Parkinson's Disease.

The functions of platelets are broad. Platelets function in hemostasis and thrombosis, inflammation and immune responses, vascular regulation, and host defense against invading pathogens, among others. These actions are achieved through the release of a wide set of coagulative, vascular, inflammatory, and other factors as well as diverse cell surface receptors involved in the same activities. As active participants in these physiological processes, platelets become involved in signaling pathways and pathological reactions that contribute to diseases that are defined by inflammation (including by pathogen-derived stimuli), vascular dysfunction, and coagulation. These diseases include Alzheimer's and Parkinson's disease, the two most common neurodegenerative diseases. Despite their unique pathological and clinical features, significant shared pathological processes exist between these two conditions, particularly relating to a central inflammatory mechanism involving both neuroinflammation and inflammation in the systemic environment, but also neurovascular dysfunction and coagulopathy, processes which also share initiation factors and receptors. This triad of dysfunction-(neuro)inflammation, neurovascular dysfunction, and hypercoagulation-illustrates the important roles platelets play in neuropathology. Although some mechanisms are understudied in Alzheimer's and Parkinson's disease, a strong case can be made for the relevance of platelets in neurodegeneration-related processes.

Six distinct NFκB signaling codons convey discrete information to distinguish stimuli and enable appropriate macrophage responses

SUMMARYMacrophages initiate inflammatory responses via the transcription factor NFκB. The temporal pattern of NFκB activity determines which genes are expressed and thus, the type of response that ensues. Here, we examined how information about the stimulus is encoded in the dynamics of NFκB activity. We generated an mVenus-RelA reporter mouse line to enable high-throughput live-cell analysis of primary macrophages responding to host- and pathogen-derived stimuli. An information-theoretic workflow identified six dynamical features—termed signaling codons—that convey stimulus information to the nucleus. In particular, oscillatory trajectories were a hallmark of responses to cytokine but not pathogen-derived stimuli. Single-cell imaging and RNA sequencing of macrophages from a mouse model of Sjögren’s syndrome revealed inappropriate responses to stimuli, suggestive of confusion of two NFκB signaling codons. Thus, the dynamics of NFκB signaling classify immune threats through six signaling codons, and signal confusion based on defective codon deployment may underlie the etiology of some inflammatory diseases.

Identification and Physiological Significance of Temporal Nfκb Signaling Codewords Deployed by Macrophages to Classify Immune Threats

Inflammatory pathologies often involve dysregulated macrophage functions. In health, macrophages are immune sentinels that initiate inflammatory responses via the transcription factor NFkB. The temporal pattern of NFkB activity determines which genes are expressed, but how such temporal signaling code works in primary immune cells remains unexplored. For this study, we developed tools to enable high-throughput analysis of live, primary macrophages responding to host- and pathogen-derived stimuli. An information-theoretic workflow identified six dynamical features that constitute codewords that convey stimulus information to the nucleus. In particular, oscillatory trajectories are a hallmark of the responses to host cytokine TNF. Remarkably, examining macrophages derived from a systemic autoimmune disease model suggests that confusion of two NFkB signaling codewords, and thus miscoding of TNF as a pathogen-derived stimulus, may underlie sporadic inflammatory pathology. Overall, this study identifies six codewords of the temporal NFkB signaling code for classifying immune threats and demonstrates their biological significance.

Physiological Regulation of Innate Lymphoid Cells.

Discovery of innate lymphoid cells (ILCs) have provoked a paradigm shift in our understanding of the immune protection. Their constitutive presence and activity at the body's barrier surfaces ensure the maintenance of the tissue homeostasis and immune protection. This complex family has distinct and non-redundant functions that can have both beneficial and detrimental effects on disease outcome. The capacity of ILCs to perform their function effectively relies on their ability to sense and integrate intrinsic and extrinsic signals. Recent studies have shown that ILCs are not only sensitive to pathogen-derived stimuli but are also very well equipped to sense host-derived signals such as neuropeptides, hormones, and metabolites. The integration of these signals represents a complex and constant cross-talk between the immune system and the physiological systems of the body, including the nervous, endocrine, digestive, and reproductive systems. The physiological regulation of ILCs constitutes an important step in our understanding of the events leading to the protective and pathological properties of these cells. This review summarizes the recent advances in the understanding of the regulation of ILCs by physiological signals and their consequences on the maintenance of tissue homeostasis.

Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells.

The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models. Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands N,N-dimethyltryptamine (NN-DMT), its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cell (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses. Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1β, IL-6, TNFα and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.

Inflammation: gone with translation.

Inflammation: gone with translation.

Human conventional CD1c+ Dendritic Cells produce IL-12 and induce potent CD8+ T cell priming

Event Abstract Back to Event Human conventional CD1c+ Dendritic Cells produce IL-12 and induce potent CD8+ T cell priming Giulia Nizzoli1, Anja Weick2, Jana Krietsch2, Svenja Steinfelder2, Federica Facciotti1, Sergio Abrignani1 and Jens Geginat1* 1 INGM, Italy 2 DRFZ, Germany BDCA-3+ dendritic cells are thought to be the human equivalents of murine CD8α+ DC, which cross-prime CD8+ T-cell responses and secrete high amounts of IL-12. We compared human myeloid DC expressing CD1c or BDCA-3 and plasmacytoid DC for cytokine production and surface receptor expression in peripheral blood and lymphoid tissues, and assessed their capacities to induce cytotoxic T cell responses. We found that mDC1, but not other DC or monocyte subsets could secrete high amounts of IL-12p70. IL-12 production by mDC1 was tightly controlled, as it required combinational Toll-like receptor (TLR) stimulation and was fine-tuned by lymphocyte-derived stimuli. Conversely, mDC2 produced high levels of IFNlambda in response to TLR-3 stimulation alone. pDC secreted IFNalpha  expressed lower levels of MHC class-I and -II, CD40 and CD86 than myeloid DC. Moreover, they poorly cross-presented soluble antigens to CD8+ T cells. In contrast, both mDC1 and mDC2 could cross-present efficiently, but required different combinations of TLR ligands. Nevertheless, all DC subsets induced secondary expansions of CD8+ memory T-cells upon licensing by CD4+ T-cells. Furthermore, following appropriate TLR stimulation and help by CD4+ T cells, all DC primed naive CD8+ T-cells. However, while mDC1 induced high levels of Granzyme B via IL-12, mDC2 and pDC induced preferentially Granzyme A. Our results show that CD1c+ mDC1 are a relevant source of IL-12 for naïve T cell priming, and that specific pathogen-derived stimuli and CD4 help can instruct different DC subsets to induce cytotoxic T-cell responses. Keywords: human DC subsets, IL-12p70, cross-presentation, CD8+ priming, MDC1 Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Innate immunity Citation: Nizzoli G, Weick A, Krietsch J, Steinfelder S, Facciotti F, Abrignani S and Geginat J (2013). Human conventional CD1c+ Dendritic Cells produce IL-12 and induce potent CD8+ T cell priming. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00876 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 21 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Jens Geginat, INGM, Milano, Italy, geginat@ingm.org Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Giulia Nizzoli Anja Weick Jana Krietsch Svenja Steinfelder Federica Facciotti Sergio Abrignani Jens Geginat Google Giulia Nizzoli Anja Weick Jana Krietsch Svenja Steinfelder Federica Facciotti Sergio Abrignani Jens Geginat Google Scholar Giulia Nizzoli Anja Weick Jana Krietsch Svenja Steinfelder Federica Facciotti Sergio Abrignani Jens Geginat PubMed Giulia Nizzoli Anja Weick Jana Krietsch Svenja Steinfelder Federica Facciotti Sergio Abrignani Jens Geginat Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Leukocyte – endothelial interactions in inflammation

At sites of inflammation, infection or vascular injury local proinflammatory or pathogen-derived stimuli render the luminal vascular endothelial surface attractive for leukocytes. This innate immunity response consists of a well-defined and regulated multi-step cascade involving consecutive steps of adhesive interactions between the leukocytes and the endothelium. During the initial contact with the activated endothelium leukocytes roll along the endothelium via a loose bond which is mediated by selectins. Subsequently, leukocytes are activated by chemokines presented on the luminal endothelial surface, which results in the activation of leukocyte integrins and the firm leukocyte arrest on the endothelium. After their firm adhesion, leukocytes make use of two transmigration processes to pass the endothelial barrier, the transcellular route through the endothelial cell body or the paracellular route through the endothelial junctions. In addition, further circulating cells, such as platelets arrive early at sites of inflammation contributing to both coagulation and to the immune response in parts by facilitating leukocyte–endothelial interactions. Platelets have thereby been implicated in several inflammatory pathologies. This review summarizes the major mechanisms and molecules involved in leukocyte–endothelial and leukocyte-platelet interactions in inflammation.

Autophagy and the Immune Response to TB

Autophagy is a homeostatic mechanism for the catabolism of cytosolic constituents, including organelles, in times of stress and nutrient deprivation. In addition, autophagy has been linked to innate and adaptive immune responses to numerous infectious microorganisms, including mycobacteria. This review explores the role of autophagy in the responses of antigen-presenting cells to mycobacteria, including links with phagosome maturation, inflammasome activation and antigen presentation. In addition, the modulation of autophagy by cytokines and pathogen-derived stimuli is discussed.

Common variants in NLRP2 and NLRP3 genes are strong prognostic factors for the outcome of HLA-identical sibling allogeneic stem cell transplantation

AbstractThe inflammasomes are macromolecular cytosolic complexes involved in the production of interleukin-1β (IL-1β) and IL-18 in response to several pathogen-derived stimuli. Such interleukins have been implicated in the origin of severe allogeneic stem cell transplant (allo-SCT) complications. We analyzed the relationship between the interindividual variability in inflammasome protein-encoding genes in donors and patients and clinical outcome after allo-SCT. Fourteen common genetic variants in 5 genes of the inflammasome, namely, NLRP1, NLRP2, NLRP3, CARD8, and CASP5, were genotyped in 133 human leukocyte antigen-identical sibling pairs undergoing allo-SCT. In the multivariate analysis, donor variants in NLRP2 and NLRP3 were the most important prognostic factors for the clinical outcome after allo-SCT. Thus, donor TT genotype at rs10925027 in NLRP3 was associated with disease relapse (odds ratio (OR) = 6.3, P = 1 × 10−7), and donor GG genotype at rs1043684 in NLRP2 was associated with nonrelapse mortality (OR = 4.4, P = 6 × 10−4) and overall survival (OR = 3.1, P = .001). In addition, patient AA genotype at rs5862 in NLRP1 was associated with nonrelapse mortality (OR = 2.8, P = .005) and overall survival (OR = 2.0, P = .009). These results suggest that inflammasome genetic variants are important prognostic factors for the outcome of allo-SCT. If validated in larger studies, including unrelated allo-SCT, NLRPs genotype would become an important factor in donor selection.

Erythromycin Differentially Inhibits Lipopolysaccharide- or Poly(I:C)-Induced but Not Peptidoglycan-Induced Activation of Human Monocyte-Derived Dendritic Cells

Erythromycin (EM) has attracted attention because of its anti-inflammatory effect. Because dendritic cells (DCs) are the most potent APCs involved in numerous pathologic processes including innate immunity, we examined effects of EM on the activation of human DCs by pathogen-derived stimuli. Monocyte-derived DCs were pretreated with EM and subsequently stimulated with peptidoglycan, polyriboinosinic:polyribocytidylic acid (poly(I:C)), or LPS. The activation of DCs was assessed by surface molecule expression and cytokine production. To reveal the signaling pathways affected by EM, TLR expression, NF-kappaB, IFN regulatory factor-3, and AP-1 activation were examined. EM inhibited costimulatory molecule expression and cytokine production that was induced by poly(I:C) and LPS but not by peptidoglycan. EM pretreatment down- and up-regulated mRNA levels of TLR3 and TLR2, respectively, but did not affect that of TLR4. EM suppressed IFN regulatory factor-3 activation and IFN-beta production but not AP-1 activation induced by poly(I:C) and LPS. The inhibitory effect of EM on NF-kappaB activation was observed only in poly(I:C)-stimulated DCs. EM selectively suppressed activation of DCs induced by LPS and poly(I:C) in different ways, suggesting that the immuno-modulating effects of EM depend on the nature of pathogens. These results might explain why EM prevents the virus-induced exacerbation in the chronic inflammatory respiratory diseases and give us the clue to design new drugs to treat these diseases.

Suppressors of cytokine signaling (SOCS)-1 and SOCS-3 are induced by CpG-DNA and modulate cytokine responses in APCs.

During infection, the functional status of the innate immune system is tightly regulated. Although signals resulting in activation have been well characterized, counterregulative mechanisms are poorly understood. Suppressor of cytokine signaling (SOCS) proteins have been characterized as cytokine-inducible negative regulators of Janus kinase/STAT signaling in cells of hemopoietic origin. To analyze whether SOCS proteins could also be induced by pathogen-derived stimuli, we investigated the induction of SOCS-1 and SOCS-3 after triggering of macrophage cell lines, bone marrow-derived dendritic cells, and peritoneal macrophages with CpG-DNA. In this study, we show that CpG-DNA, but not GpC-DNA, induces expression of mRNA for SOCS-1 and SOCS-3 in vitro and in vivo. SOCS mRNA expression could be blocked by chloroquine and was independent of protein synthesis. Inhibitors of the mitogen-activated protein kinase pathway triggered by CpG-DNA were able to impede induction of SOCS mRNA. CpG-DNA triggered synthesis of SOCS proteins that could be detected by Western blotting. SOCS proteins were functional because they inhibited IFN-gamma as well as IL-6- and GM-CSF-induced phosphorylation of STAT proteins. Furthermore, IFN-gamma-induced up-regulation of MHC class II molecules was also prevented. The same effects could be achieved by overexpression of SOCS-1. Hence, the results indicate a substantial cross-talk between signal pathways within cells. They provide evidence for regulative mechanisms of Janus kinase/STAT signaling after triggering Toll-like receptor signal pathways.

Conditioning of Dendritic Cells by Pathogen-Derived Stimuli

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