Signaling Through Nucleic Acid Sensors and Their Roles in Inflammatory Diseases

Okude, Haruna; Ori, Daisuke; Kawai, Taro

doi:10.3389/fimmu.2020.625833

Cited by 80 publications

(51 citation statements)

References 258 publications

(310 reference statements)

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“…The cytosolic RNA-sensing signaling pathway is an important antiviral innate immune mechanism that responds to invading viral RNAs, leading to type I IFN and interferon stimulated gene (ISG) expressions ( 1 , 2 ). Deregulation of this signaling pathway may result in autoimmune diseases if it reacts to cellular self RNAs ( 3 , 4 ). It has been found that deficiency of the RNA-editing enzyme ADAR1 activates this innate immune signaling pathway and enhances ISG expression in mouse embryos ( 5 , 6 ).…”

Section: Introductionmentioning

confidence: 99%

ADAR1 RNA editing regulates endothelial cell functions via the MDA-5 RNA sensing signaling pathway

et al. 2021

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The RNA-sensing signaling pathway has been well studied as an essential antiviral mechanism of innate immunity. However, its role in non-infected cells is yet to be thoroughly characterized. Here, we demonstrated that the RNA sensing signaling pathway also reacts to the endogenous cellular RNAs in endothelial cells (ECs), and this reaction is regulated by the RNA-editing enzyme ADAR1. Cellular RNA sequencing analysis showed that EC RNAs endure extensive RNA editing, especially in the RNA transcripts of short interspersed nuclear elements. The EC-specific deletion of ADAR1 dramatically reduced the editing level on short interspersed nuclear element RNAs, resulting in newborn death in mice with damage evident in multiple organs. Genome-wide gene expression analysis revealed a prominent innate immune activation with a dramatically elevated expression of interferon-stimulated genes. However, blocking the RNA sensing signaling pathway by deletion of the cellular RNA receptor MDA-5 prevented interferon-stimulated gene expression and rescued the newborn mice from death. This evidence demonstrated that the RNA-editing/RNA-sensing signaling pathway dramatically modulates EC function, representing a novel molecular mechanism for the regulation of EC functions.

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Section: Introductionmentioning

confidence: 99%

ADAR1 RNA editing regulates endothelial cell functions via the MDA-5 RNA sensing signaling pathway

et al. 2021

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“…Through knock-out of IFNAR, we found the B cell intrinsic action of type I IFN to be expendable for their GC participation. In addition, the two signaling pathways converge, albeit ostensibly via different routes, on the activation of MAPK/AP-1 and NF-κB, which promote production of proinflammatory cytokines, survival, and proliferation of the cell ( 54 ). Despite their downstream overlap in effector functions, the TLR7 and STING pathways are compartmentalized very differently in the host cell, with topological equivalence and inequivalence, respectively, to the subcellular localization of the BCR.…”

Section: Discussionmentioning

confidence: 99%

B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation

et al. 2021

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Germinal centers (GCs) are induced microanatomical structures wherein B cells undergo affinity maturation to improve the quality of the antibody response. Although GCs are crucial to appropriate humoral responses to infectious challenges and vaccines, many questions remain about the molecular signals driving B cell participation in GC responses. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an important mediator of type I interferon and proinflammatory cytokine responses during infection and cellular stress. Recent studies have reported important roles for STING in B cell responses, including an impact on GC B cells and downstream antibody responses, which could have great consequences for vaccine design and understanding STING-associated interferonopathies. GCs are also involved in untoward reactions to autoantigens in a plethora of autoimmune disorders, and it is generally thought that these responses coopt the mechanisms used in foreign antigen-directed GCs. Here, we set out to investigate the importance of the cGAS-STING pathway in autoreactive B cell responses. In a direct competition scenario in a murine mixed bone marrow chimera model of autoreactive GCs, we find that B cell intrinsic deficiency of cGAS, STING, or the type I interferon receptor IFNAR, does not impair GC participation, whereas Toll-like receptor (TLR)-7 deficiency mediates a near-complete block. Our findings suggest that physiological B cell responses are strictly sustained by signals linked to BCR-mediated endocytosis. This wiring of B cell signals may enable appropriate antibody responses, while at the same time restricting aberrant antibody responses during infections and in autoimmune or autoinflammatory settings.

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“…The immunogenic property of mRNA is both beneficial and detrimental for mRNA vaccines. The presence of nucleic acid sensors, such as TLR3, TLR7/8, RIG-I, and MDA-5, recognize vaccinated mRNA, which then proceed to activate innate immune signaling pathways to produce type-I IFNs (Okude et al, 2020). As mentioned previously, activation of innate immunity is crucial for the development of adaptive immunity against the intended vaccine target.…”

Section: Mrna Vaccines and Adjuvantsmentioning

confidence: 99%

Exploration of Pattern Recognition Receptor Agonists as Candidate Adjuvants

Ong

Lian

Kawasaki

et al. 2021

Front. Cell. Infect. Microbiol.

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Adjuvants are used to maximize the potency of vaccines by enhancing immune reactions. Components of adjuvants include pathogen-associated molecular patterns (PAMPs) and damage-associate molecular patterns (DAMPs) that are agonists for innate immune receptors. Innate immune responses are usually activated when pathogen recognition receptors (PRRs) recognize PAMPs derived from invading pathogens or DAMPs released by host cells upon tissue damage. Activation of innate immunity by PRR agonists in adjuvants activates acquired immune responses, which is crucial to enhance immune reactions against the targeted pathogen. For example, agonists for Toll-like receptors have yielded promising results as adjuvants, which target PRR as adjuvant candidates. However, a comprehensive understanding of the type of immunological reaction against agonists for PRRs is essential to ensure the safety and reliability of vaccine adjuvants. This review provides an overview of the current progress in development of PRR agonists as vaccine adjuvants, the molecular mechanisms that underlie activation of immune responses, and the enhancement of vaccine efficacy by these potential adjuvant candidates.

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Signaling Through Nucleic Acid Sensors and Their Roles in Inflammatory Diseases

Cited by 80 publications

References 258 publications

ADAR1 RNA editing regulates endothelial cell functions via the MDA-5 RNA sensing signaling pathway

ADAR1 RNA editing regulates endothelial cell functions via the MDA-5 RNA sensing signaling pathway

B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation

Exploration of Pattern Recognition Receptor Agonists as Candidate Adjuvants

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