Toll-like Receptors and the Control of Immunity

Fitzgerald, Katherine A.; Kagan, Jonathan C.

doi:10.1016/j.cell.2020.02.041

Cited by 1,451 publications

(1,261 citation statements)

References 271 publications

(350 reference statements)

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“…Cytosolic PRRs, including RIG‐I‐like receptors (RLRs) that detect RNA, AIM2‐like receptors (ALRs), and cyclic GMP‐AMP synthase (cGAS) which sense DNA, play critical roles in inducing signaling cascades to mediate host defenses 16 . Membrane‐bound PRRs, including TLRs and CLRs, are extensively reviewed elsewhere, 11,17,18 Cytosolic receptors, including NLRs, RLRs, ALRs, RLRs, cGAS, and STING, will be further discussed in the present review.…”

Section: Structure and Function Of Innate Pattern Recognition Receptorsmentioning

confidence: 99%

The microbiome and cytosolic innate immune receptors

Liwinski

Zheng

Elinav

2020

Immunological Reviews

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The discovery of innate immune sensors (pattern recognition receptors, PRRs) has profoundly transformed the notion of innate immunity, in providing a mechanistic basis for host immune interactions with a wealth of environmental signals, leading to a variety of immune‐mediated outcomes including instruction and activation of the adaptive immune arm. As part of this growing understanding of host‐environmental cross talk, an intimate connection has been unveiled between innate immune sensors and signals perceived from the commensal microbiota, which may be regarded as a hub integrating a variety of environmental cues. Among cytosolic PRRs impacting on host homeostasis by interacting with the commensal microbiota are nucleotide‐binding domain, leucine‐rich repeat‐containing protein receptors (NLRs), together with a number of cytosolic DNA sensors and the family of absent in melanoma (AIM)–like receptors (ALRs). NLR sensors have been a particular focus of research, and some NLRs have emerged as key orchestrators of inflammatory responses and host homeostasis. Some NLRs achieve this through the formation of cytoplasmic multiprotein complexes termed inflammasomes. More recently discovered PRRs include retinoic acid‐inducible gene‐I (RIG‐I)–like receptors (RLRs), cyclic GMP‐AMP synthase (cGAS), and STING. In the present review, they summarize recent advancements in knowledge on structure and function of cytosolic PRRs and their roles in host‐microbiota cross talk and immune surveillance. In addition, we discuss their relevance for human health and disease and future therapeutic applications involving modulation of their activation and signaling.

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Section: Structure and Function Of Innate Pattern Recognition Receptorsmentioning

confidence: 99%

The microbiome and cytosolic innate immune receptors

Liwinski

Zheng

Elinav

2020

Immunological Reviews

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“…TLR often act in the form of homo-or heterodimers, and play a role in clearing infections. Some TLR types are expressed on the cell surface, but the ones present on intracellular membranes of endosomes (TLR3, 7, 8, and 9) are intended to register, though not exclusively, viral infections by detecting foreign types of nucleic acids (Fitzgerald and Kagan 2020). The nuclear material of coronaviruses is single-stranded RNA (ssRNA).…”

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confidence: 99%

COVID-19 pandemic: is a gender-defined dosage effect responsible for the high mortality rate among males?

Groot

Bontrop

2020

Immunogenetics

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“…16 Among various in ammatory mediators, TLR is considered crucial in innate immune system as a rst-line defense and mediator of in ammation. 17,18 Exogenous/endogenous TLR ligands such as heat shock proteins, brinogen, and components of the extracellular matrix are upregulated by ischemic brain insult.…”

Section: Discussionmentioning

confidence: 99%

Propofol Ameliorates Ischemic Brain Injury by Blocking Toll-like Receptor 4-dependent Pathway and Suppressing Consequent Inflammatory Cytokine Production

Mitsui

Kotoda

Hishiyama

et al. 2020

Preprint

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BackgroundIschemic stroke is one of the leading causes of mortality and morbidity worldwide. Accumulated evidence suggests that the consequent excessive inflammation plays detrimental roles in the pathogenesis of secondary injury after cerebral infarction and exacerbates the brain tissue damage. Although regulation of the inflammation would be the potential strategy for the novel treatment option, effective methods that control the cerebral inflammation have not yet been established. Recent studies have suggested that propofol, a sedative agent widely used for management of patients with acute stroke, suppresses excessive inflammation and may have neuroprotective effects against ischemic brain injury. However, the available evidence is still limited and controversial, and the underlying mechanism remains unclear. This study aimed to investigate the neuroprotective effects of propofol against ischemic brain injury, with a specific focus on Toll-like receptor 4 (TLR4), the critical mediator of inflammation in the ischemic brain.ResultsTreatment with propofol significantly reduced infarct volume in wild-type mice (7.9 ± 1.4 vs. 12.6 ± 1.1 mm3, n = 10 each, p < 0.05). The propofol-treated mice exhibited lower levels of pro-inflammatory cytokine expressions compared with the control mice (IL-6: 0.57 ± 0.23 vs. 1.00 ± 0.39, p < 0.05, IL-1β: 0.53 ± 0.24 vs. 1.00 ± 0.36, p = 0.087, n = 15 each). The neuroprotective effect of propofol was abrogated by TLR4 gene knockout. Propofol treatment had no significant effects on hemodynamic parameters.ConclusionsPropofol attenuates brain injury by blocking the TLR4-dependent pathway and suppressing pro-inflammatory cytokine production. This insight into the mechanism underlying the neuroprotective effect of propofol against ischemic brain injury may lead to a new strategy for preventing exacerbation of cerebral infarction.

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Toll-like Receptors and the Control of Immunity

Cited by 1,451 publications

References 271 publications

The microbiome and cytosolic innate immune receptors

The microbiome and cytosolic innate immune receptors

COVID-19 pandemic: is a gender-defined dosage effect responsible for the high mortality rate among males?

Propofol Ameliorates Ischemic Brain Injury by Blocking Toll-like Receptor 4-dependent Pathway and Suppressing Consequent Inflammatory Cytokine Production

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