Antigens, Bacterial ; immunology ; Drug Resistance, Bacterial ; immunology ; Signal Transduction ; immunology ; Vaccines, Subunit ; immunology

Microbial components and the endogenous molecules released from damaged cells can stimulate germ-line-encoded pattern recognition receptors (PRRs) to transduce signals to the hub of the innate immune signaling network-the adaptor proteins MyD88/TRIF/MAVS/STING/Caspase-1, where integrated signals relay to the relevant transcription factors IRF3/IRF7/NF-κB/ AP-1 and the signal transducer and activator of transcription 6 (STAT6) to trigger the expression of type I interferons and inflammatory cytokines or the assembly of inflammasomes. Most pleiotropic cytokines are secreted and bind to specific receptors, activating the signaling pathways including JAK-STAT for the proliferation, differentiation and functional capacity of immune cells. This review focuses on several critical adaptors in innate immune signaling cascades and recent progress in their molecular mechanisms.
Adaptive Immunity ; Adaptor Proteins, Signal Transducing ; immunology ; metabolism ; Animals ; Humans ; Immunity, Innate ; Signal Transduction ; immunology

The cyclic GMP-AMP (cGAMP) synthase (cGAS) has been identified as a cytosolic double stranded DNA sensor that plays a pivotal role in the type I interferon and inflammation responses via the STING-dependent signaling pathway. In the past several years, a growing body of evidence has revealed that cGAS is also localized in the nucleus where it is associated with distinct nuclear substructures such as nucleosomes, DNA replication forks, the double-stranded breaks, and centromeres, suggesting that cGAS may have other functions in addition to its role in DNA sensing. However, while the innate immune function of cGAS is well established, the non-canonical nuclear function of cGAS remains poorly understood. Here, we review our current understanding of the complex nature of nuclear cGAS and point to open questions on the novel roles and the mechanisms of action of this protein as a key regulator of cell nuclear function, beyond its well-established role in dsDNA sensing and innate immune response.
Cell Nucleus/immunology* ; Humans ; Immunity, Innate ; Nucleotidyltransferases/immunology* ; Signal Transduction/immunology*

The Notch signaling pathway is conserved from Drosophila to mammals and is critically involved in developmental processes. In the immune system, it has been established that Notch signaling regulates multiple steps of T and B cell development in both central and peripheral lymphoid organs. Relative to the well documented role of Notch signaling in lymphocyte development, less is known about its role in regulating myeloid lineage development and function, especially in the context of acute and chronic inflammation. In this review article, we will describe the evidence accumulated during the recent years to support a key regulatory role of the Notch pathway in innate immune and inflammatory responses and discuss the potential implications of such regulation for pathogenesis and therapy of inflammatory disorders.
Animals ; B-Lymphocytes ; immunology ; pathology ; Humans ; Inflammation ; immunology ; pathology ; Receptors, Notch ; immunology ; Signal Transduction ; immunology ; T-Lymphocytes ; immunology ; pathology

In this research, we studied the formation of Drosophila melanogaster FADD (Fas-associated death domain-containing protein) amyloid fiber and its influence on signal transduction in IMD (Immune deficiency) signaling pathway to better understand the regulation mechanism of Drosophila innate immune signaling pathway, which will provide reference for the immune regulation in other species. First, we purified dFADD protein expressed in Escherichia coli and performed Sulfur flavin T binding and transmission electron microscopy to identify the dFADD amyloid fibers formed in vitro. Then we investigated the formation of dFADD polymers in S2 cells using SDD-AGE and confocal microscope. We also constructed dFADD mutants to find out which domain is essential to fiber formation and its effect on IMD signal transduction. Our results revealed that dFADD could be polymerized to form amyloid fiber polymers in vitro and inside the cells. Formation of fibers relies on DED (Death-effector domain) domain of dFADD, since DED domain-deleted mutant existed as a monomer. Dual luciferase reporter assay showed that intact DED domain was required for the induction of downstream antimicrobial peptides, indicating that fiber formation was the key to IMD signal transduction. Our study revealed the role of dFADD in mediating the cascade between IMD and Dredd in the IMD signaling pathway by forming amyloid fibers, suggesting an evolutionarily conserved regulatory mechanism of innate immune signaling pathway.
Animals ; Drosophila Proteins ; biosynthesis ; immunology ; Drosophila melanogaster ; immunology ; Fas-Associated Death Domain Protein ; biosynthesis ; immunology ; Immunity, Innate ; immunology ; Signal Transduction

Polysaccharides extracted from various sources are natural active substances, which may lead to the activation of macrophage via multiple pathways and mechanisms. This article intends to illustrate the signaling pathways of polysaccharides from plants, fungi, algae and other sources, to identify the mechanisms on the molecular level, and to explore the novel target immunomodulatory agents.
Animals ; Humans ; Macrophage Activation ; drug effects ; immunology ; Macrophages ; drug effects ; immunology ; metabolism ; Polysaccharides ; pharmacology ; Signal Transduction

Interferons (IFNs) are cytokines playing an important role in immune responses. Interferons are classified into two distinct types according to specific interferon receptors(IFNR). Type I IFNs include IFN-α and IFN-β, whereas IFN-γ is type II IFN. It is well known that type I IFNs have important roles in the host defense against viruses through activation of interferon receptor A (IFNAR). However, many recent studies have also demonstrated that type I IFNs have effects on immune responses to bacterial infection. This review focuses on the immune regulation of type I IFN-mediated signal pathways in bacterial infections such as Listeria monocytogenes, Streptococcus, Mycobacterium tuberculosis, Bacillus anthracis, Legionella, Pseudomonas aeruginosa and others.
Animals ; Bacterial Infections ; immunology ; Humans ; Immunity, Innate ; Interferon Type I ; immunology ; Signal Transduction

Liver Diseases ; immunology ; metabolism ; Signal Transduction ; Toll-Like Receptors ; immunology ; metabolism

The innate immune system provides a first line of defense against invading pathogens, in which the pattern recognition receptors (PRR) recognize pathogen-associated molecular patterns (PAMP) and initiate the downstream signaling pathways to eliminate the encountered pathogens. There are two main classes of such signaling pathways: NOD-like receptor (NLR) signaling pathway and Toll-like receptor (TLR) signaling pathway. The microbial pathogens under selective pressure have evolved numerous mechanisms to avoid and/or manipulate the NLR and TLR signal transduction for survival and replication. To evade the NLR signaling pathway, pathogens interfere and/or inhibit inflammasome activation in innate immune cells by producing virulence factors or reducing PAMPs expression. The mechanisms for pathogens to evade TLR signaling pathway include: inhibition of mitogen activated protein kinases (MAPKs) cascade reaction, inhibition of NF-КB activation, and interference of down-stream signal transduction by producing Toll/interleukin-1 receptor (TIR)-containing proteins which bind directly with TLRs or adaptor proteins in the signaling pathway.
Immunity, Innate ; NLR Proteins ; immunology ; Receptors, Interleukin-1 ; metabolism ; Signal Transduction ; Toll-Like Receptors ; immunology

Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and considered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to that of its bacterial ancestor’s, consists of a circular loop and contains significant number of unmethylated DNA as CpG islands. The innate immune system plays an important role in the mammalian immune response. Recent research has demonstrated that mitochondrial DNA (mtDNA) activates several innate immune pathways involving TLR9, NLRP3 and STING signaling, which contributes to the signaling platforms and results in effector responses. In addition to facilitating antibacterial immunity and regulating antiviral signaling, mounting evidence suggests that mtDNA contributes to inflammatory diseases following cellular damage and stress. Therefore, in addition to its well-appreciated roles in cellular metabolism and energy production,mtDNA appears to function as a key member in the innate immune system. Here, we highlight the emerging roles of mtDNA in innate immunity.
Animals ; DNA, Mitochondrial ; genetics ; Humans ; Immunity, Innate ; immunology ; Mitochondria ; genetics ; immunology ; Signal Transduction