Nucleic acid-sensing TLRs: trafficking and regulation

Majer, Olivia; Liu, Bo; Barton, Gregory M.

doi:10.1016/j.coi.2016.10.003

Cited by 111 publications

(94 citation statements)

References 64 publications

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“…Thus, it was postulated that TLR7 could be functional in early endosomes prior to the development of an acidic environment. Our finding, however, that type I IFN-independent autoimmunity is dependent on AP-3 does not support a major role for early endosomal furin-processed TLR7 in autoimmunity possibly because the optimal binding of nucleic acids to TLR occurs in acidic conditions (90). Another important consideration is how relevant these findings for AP-3 in HgIA are to spontaneous autoimmune disease.…”

Section: Discussioncontrasting

confidence: 69%

“…UNC93B1 is required for trafficking nucleic acid-sensing TLRs from the endoplasmic reticulum to the appropriate endolysosomal and phagolysosomal compartments where TLRs are processed, engage ligand, and initiate signaling cascades (89, 90). However, the relative importance of TLR signaling pathways that induce type I IFN or proinflammatory cytokines, and the relevance of specific endocytic/phagocytic compartments in autoimmunity have yet to be addressed.…”

Section: Discussionmentioning

confidence: 99%

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Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN

Pollard

Escalante

Huang

et al. 2017

The Journal of Immunology

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Type I IFN and nucleic acid-sensing TLRs are both strongly implicated in the pathogenesis of lupus with most patients expressing IFN-induced genes in peripheral blood cells and with TLRs promoting type I IFNs and autoreactive B cells. About a third of SLE patients, however, lack the IFN signature suggesting the possibility of type I IFN-independent mechanisms. Here, we examined the role of type I IFN and TLR trafficking and signaling in a xenobiotic systemic autoimmunity induced by mercury (HgIA). Strikingly, autoAb production in HgIA was not dependent on the type I IFN receptor even in NZB mice that require type I IFN signaling for spontaneous disease, but was dependent on the endosomal TLR transporter UNC93B1 and the endosomal proton transporter, SLC15A4. HgIA also required the AP-3 complex, which transports TLRs from the early endosome to the late endolysosomal compartments. Examination of TLR signaling pathways implicated the canonical NF-κB pathway and the proinflammatory cytokine IL-6 in autoantibody production, but not IRF7. These findings identify HgIA as a novel type I IFN-independent model of systemic autoimmunity and implicate TLR-mediated NF-κB proinflammatory signaling from the late endocytic pathway compartments in autoAb generation.

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Section: Discussioncontrasting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN

Pollard

Escalante

Huang

et al. 2017

The Journal of Immunology

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“…1,18 Nucleic-acid sensors in endolysosomes (endosomal sensors) and the cytosol (cytosolic sensors) recognize foreign and self-nucleic acids. 1,24 Engagement of endosomal or cytosolic sensors trigger inflammatory responses by initiating a signaling pathways that activate several transcription factors such as nuclear factor kappa-B (NF-KB), IRF3, IRF7 and AP-1 that promote production of type I interferons and inflammatory cytokines including interleukin (IL)-1, IL-6, IL-12 and tumor necrosis factor (TNF). 1 Pro-inflammatory cytokines triggered by endosomal or cytosolic sensors contribute to synovial cartilage and bone destruction in RA.…”

mentioning

confidence: 99%

The genetic pathogenesis, diagnosis and therapeutic insight of rheumatoid arthritis

Zamanpoor

2019

Clinical Genetics

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Rheumatoid arthritis (RA) is a systemic autoimmune disease that causes chronic inflammation of the joints. RA is a heterogeneous disorder caused by an abnormal autoimmune response triggered by the complex interactions of genetic and environmental factors that contribute to RA etiology. However, its underlying pathogenic mechanisms are yet to be fully understood. In this review, I provide an overview of the pathogenesis, diagnosis and therapeutic insight in the clinical management of RA in light of the recent updates to classification criteria and recent discoveries of genetic loci associated with susceptibility for RA.

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“…PRRs that detect extracellular PAMPs are commonly activated by microbes, regardless of their virulence potential, and include the TLRs and Dectin families (Kagan, 2012). TLRs, in particular, survey the extracellular space and the contiguous luminal compartments of endosomal vesicles for PAMPs (Majer et al, 2016). These microbial products range from bacterial cell surface components ( e.g.…”

Section: Pamps From Non-infectious Microbes Induce a Generic Phagocytmentioning

confidence: 99%

Innate Immune Receptors as Competitive Determinants of Cell Fate

Franz

Kagan

2017

Molecular Cell

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Infections can cause a multitude of stresses on the host and microbe. To detect potential infections, the mammalian immune system utilizes several families of pattern recognition receptors, which survey the intracellular and extracellular environments for microbial products. Members of each receptor family induce antimicrobial effector responses, which include inflammatory cytokine or interferon expression, downregulation of protein synthesis or host cell death. In this Review, we discuss the benefits of each of these innate immune responses. We highlight how non-infectious bacteria and viruses typically activate a single family of receptors, which results in a predictable host response. Infections with virulent pathogens, in contrast, may activate receptors from distinct families. As each receptor family may induce responses that antagonize or synergize with the activities of another family, cell fate decisions during pathogenic encounters are unpredictable. Understanding the antagonistic antimicrobial activities of the innate immune system should provide insight into how cell fate decisions are made during infections, and potentially during other environmental stresses.

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Nucleic acid-sensing TLRs: trafficking and regulation

Cited by 111 publications

References 64 publications

Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN

Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN

The genetic pathogenesis, diagnosis and therapeutic insight of rheumatoid arthritis

Innate Immune Receptors as Competitive Determinants of Cell Fate

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