Neurotransmitter suppression of the in vitro generation of a cytotoxic T lymphocyte response against the syngeneic MOPC-315 plasmacytoma

We have previously shown that, as a consequence of low-dose melphalan (l-phenylalanine mustard (l-PAM) therapy, the hitherto immunosuppressed spleen cells from BALB/c mice bearing a large MOPC-315 tumor (in contrast to spleen cells from normal mice) acquire the ability to generate a greatly enhanced anti-MOPC-315 cytotoxic T lymphocyte (CTL) response upon in vitro stimulation with MOPC-315 tumor cells. Here we show that the catecholamines norepinephrine, epinephrine, and isoproterenol suppressed the in vitro generation of anti-MOPC-315 cytotoxicity by spleen cells from mice that had just completed the eradication of a large MOPC-315 tumor following low-dosel-PAM therapy (l-PAM TuB spleen cells), as well as by spleen cells from normal mice. In contrast to the marked suppression obtained with catecholamines, the cholinergic agonist carbachol had no effect on the in vitro generation of splenic anti-MOPC-315 cytotoxicity. The inhibitory effect of the catecholamines was mimicked by the membranepenetrating analog of cAMP, dibutyryl-cAMP, and by cholera toxin at concentrations that stimulate the endogenous production of cAMP. The -adrenergic receptor antagonist propranolol did not block norepinephrine-induced inhibition of the generation of anti-MOPC-315 cytotoxicity by either normal orl-PAM TuB spleen cells. Since the curative effectiveness of low-dosel-PAM therapy for MOPC-315 tumor bearers requires the participation of CD8⁺ T cells that exploit a CTL response in tumor eradication, it is conceivable that norepinephrine may reduce the therapeutic outcome of low-dose chemotherapy by inhibiting the acquisition of CTL activity.     

Identification of nucleoporin 93 (Nup93) that mediates antiviral innate immune responses

RIG-I-like receptors (RLRs) are cytoplasmic sensors for viral RNA that elicit antiviral innate immune responses. RLR signaling culminates in the activation of the protein kinase TBK1, which mediates phosphorylation and nuclear translocation of IRF3 that regulates expression of type I interferon genes. Here, we found that Nucleoporin 93 (Nup93), components of nuclear pore complex (NPC), plays an important role in RLR-mediated antiviral responses. Nup93-deficient RAW264.7 macrophage cells exhibited decreased expression of Ifnb1 and Cxcl10 genes after treatment with a synthetic RLR agonist stimulation as well as Newcastle Disease Virus infection. Silencing Nup93 in murine primary macrophages and embryonic fibroblasts also resulted in reduced expression of these genes. IRF3 nuclear translocation during RLR signaling was impaired in Nup93-deficient RAW264.7 cells. Notably, the activation of TBK1 during RLR signaling was also decreased in Nup93-deficient cells. We found that Nup93 formed a complex with TBK1, and Nup93 overexpression enhanced TBK1-mediated IFNβ promoter activation. Taken together, our findings suggest that Nup93 regulates antiviral innate immunity by enhancing TBK1 activity and IRF3 nuclear translocation.     

RIG-I family RNA helicases: cytoplasmic sensor for antiviral innate immunity

Viral infection is detected by cellular sensors as foreign nucleic acid and initiates innate antiviral responses, including the activation of type I interferon (IFN) and proinflammatory cytokines. Recent advances in cytoplasmic virus sensors highlight their essential role in the induction of innate immunity. Moreover, it is intriguing to understand how they can discriminate innate RNA from viral foreign RNA. In this mini-review, we focus on these cytoplasmic virus sensors, termed retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs), and discuss their function in the innate immune system.     

Regulation of RLR-mediated innate immune signaling--it is all about keeping the balance

The current view of cytoplasmic RNA-mediated innate immune signaling involves the differential activation of the RNA helicases retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology-2 (LGP2) by distinct RNA viruses. RIG-I, MDA5 and LGP2 form the RIG-I like receptor family (RLR). Since the initial characterization of the RLRs rapid progress has been made in the understanding of the molecular mechanisms that upon virus infection lead to the activation of downstream signaling cascades and the subsequent induction of type I interferon (IFN) and proinflammatory cytokines by these receptors. However, antiviral responses must be tightly regulated in order to prevent uncontrolled production of type I IFN that might have deleterious effects on the host. Exploring the structural and molecular mechanisms that underlie RLR signaling thus was accompanied by the discovery of how RLR-dependent antiviral responses are modulated. This article summarizes the current understanding of endogenous regulation in RLR signaling by various intrinsic molecules that exert their regulatory function in both the steady state or upon viral infection by targeting multiple steps of the signaling cascade.     

Thematic review series: the immune system and atherogenesis. Immune function in atherogenesis

In this overview to a new thematic series on the immune system and atherogenesis, I provide a very brief summary of current conceptions of atherogenesis, of the innate and adaptive immune systems, and of the participation of the latter in atherogenesis, with particular emphasis on studies of the involvement of the immune system in atherosclerosis reported in the last 2 years. This is followed by a short outline of the eight reviews that will make up this thematic series. The overview is concluded with some caveats that should be considered in the analysis of atherosclerosis in experimental animals.     

Brain heterogeneity leads to differential innate immune responses and modulates pathogenesis of viral infections

The central nervous system (CNS) is a highly complex organ with highly specialized cell subtypes. Viral infections often target specific structures of the brain and replicate in certain regions. Studies in mice deficient in type I Interferon (IFN) receptor or IFN-β have highlighted the importance of the type I IFN system against viral infections and non-viral autoimmune disorders in the CNS. Direct antiviral effects of type I IFNs appear to be crucial in limiting early spread of a number of viruses in CNS tissues. Increased efforts have been made to characterize IFN expression and responses in the brain. In this context, it is important to identify cells that produce IFN, decipher pathways leading to type I IFN expression and to characterize responding cells. In this review we give an overview about region specific aspects that influence local innate immune responses. The route of entry is critical, but also the susceptibility of different cell types, heterogeneity in subpopulations and micro-environmental cues play an important role in antiviral responses.Recent work has outlined the tremendous importance of type I IFNs, particularly in the limitation of viral spread within the CNS. This review will address recent advances in understanding the mechanisms of local type I IFN production and response, in the particular context of the CNS.     

Activation and regulation of pathogen sensor RIG-I

Cells are equipped with a large set of pattern recognition receptors or sensors that detect foreign molecules such as pathogenic nucleic acids and initiate proinflammatory and antimicrobial innate immune responses. RIG-I is a cytosolic sensor that detects 5′-triphosphate double-stranded RNAs produced during infection. RIG-I is responsible for mounting an antimicrobial response against a variety of viruses and intracellular bacteria. RIG-I contains an intricate structural architecture that allows for efficient signaling downstream in the pathway and autoregulation. The RIG-I-mediated antimicrobial pathway is highly regulated in cells requiring various cofactors, negative regulators, and posttranslational modifications. Modulation of RIG-I and RIG-I-mediated signaling in cells by pathogens to evade recognition and activation of the antimicrobial pathway highlights the essential nature of RIG-I in the innate immune response.     

DNA模式识别受体研究进展

固有免疫系统利用模式识别受体识别病原相关分子模式。近期研究发现,外源DNA能够被宿主细胞中多种DNA受体识别,激活多种信号通路,上调Ⅰ型干扰素和促炎性细胞因子的表达。基于DNA的免疫识别在激活宿主抗感染免疫过程中起重要作用,因此仅对现已报道的DNA受体进行概述,同时对DNA的免疫识别与自身免疫病之间的关系进行探讨。     

Abnormal regulation of the antiviral response in neurological/neurodegenerative diseases

Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis are a few examples of debilitating neurological/neurodegenerative diseases for which there are currently no curative treatments. Recent evidence has strongly suggested a role for neuroinflammation in both the onset and progression of these diseases. However, the mechanisms that initiate neuroinflammation are presently unclear. Mounting evidence suggests that environmental factors are likely involved. One proposed mechanism linking both genetic and environmental factors is dysregulation of the antiviral response. Indeed, many mutations that have been linked to neurological conditions occur in genes related to the antiviral response. Although the products of these genes may have potent antiviral activities – they can also have deleterious effects when their expression is not appropriately regulated. For that reason, expression of antiviral genes is a tightly controlled process. Herein, we review the various antiviral genes that have been linked to neurological conditions. We focus specifically on type I interferonopathies, the symptoms of which are often evident at birth, and neurodegenerative diseases, which frequently onset later in life.