Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity

Duan, Tianhao; Du, Yang; Xing, Changsheng; Wang, Helen Y.; Wang, Rongfu

doi:10.3389/fimmu.2022.812774

Cited by 383 publications

(232 citation statements)

References 335 publications

(331 reference statements)

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“…Based on our findings, which show that TIRAP silencing had the most prominent inhibitory effect on the expression and secretion of the IRF5-regulated cytokines IFNβ and IL-12p70 ( Figure 1 , Figure 2 and Figure 3 ), we addressed TLR8-mediated nuclear translocation of the transcription factors NF-κB p65/RelA (p65) and IRF5 after the stimulation of cells by the CL075 ligand. NF-κB, a heterodimer with p65 as one of the components of the dimer, mainly induces the expression of pro-inflammatory cytokines, such as TNF and IL-6 [ 1 , 36 ]. In human monocytes and MDMs, TLR8 induces expression of IFNβ and IL-12A genes in an IRF5-dependent manner, while TNF is less affected by IRF5 silencing [ 13 , 26 , 27 ].…”

Section: Resultsmentioning

confidence: 99%

TIRAP/Mal Positively Regulates TLR8-Mediated Signaling via IRF5 in Human Cells

et al. 2022

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Toll-like receptor 8 (TLR8) recognizes single-stranded RNA of viral and bacterial origin as well as mediates the secretion of pro-inflammatory cytokines and type I interferons by human monocytes and macrophages. TLR8, as other endosomal TLRs, utilizes the MyD88 adaptor protein for initiation of signaling from endosomes. Here, we addressed the potential role of the Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP) in the regulation of TLR8 signaling in human primary monocyte-derived macrophages (MDMs). To accomplish this, we performed TIRAP gene silencing, followed by the stimulation of cells with synthetic ligands or live bacteria. Cytokine-gene expression and secretion were analyzed by quantitative PCR or Bioplex assays, respectively, while nuclear translocation of transcription factors was addressed by immunofluorescence and imaging, as well as by cell fractionation and immunoblotting. Immunoprecipitation and Akt inhibitors were also used to dissect the signaling mechanisms. Overall, we show that TIRAP is recruited to the TLR8 Myddosome signaling complex, where TIRAP contributes to Akt-kinase activation and the nuclear translocation of interferon regulatory factor 5 (IRF5). Recruitment of TIRAP to the TLR8 signaling complex promotes the expression and secretion of the IRF5-dependent cytokines IFNβ and IL-12p70 as well as, to a lesser degree, TNF. These findings reveal a new and unconventional role of TIRAP in innate immune defense.

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Section: Resultsmentioning

confidence: 99%

TIRAP/Mal Positively Regulates TLR8-Mediated Signaling via IRF5 in Human Cells

et al. 2022

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“…So, the TLR4 immunoreactivity detected in our study could be indicative of signaling from both the membrane through Myd88 and internally from TRIF, as well as the MyD88 immunoreactivity could be somehow non-specific for TLR4 and may include other TLRs (Biswas, 2018). Nevertheless, even if different pathways are activated, all of them converge and activate the NF-κB factor, in which we are particularly interested because it is the foremost important transcriptional manager of inflammation-associated genes (Marongiu et al, 2019;Ciesielska et al, 2021;Lin et al, 2021;Duan et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: findings in preclinical models and in a postmortem human case”

Moya

Escudero

Gómez-Blázquez

et al. 2022

Preprint

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Wernicke encephalopathy (WE) is a neurologic disease caused by vitamin B1 or thiamine deficiency (TD), being the alcohol use disorder (AUD) its main risk factor. WE patients present limiting motor, cognitive and emotional alterations related to a selective cerebral vulnerability. Neuroinflammation has been proposed as one of the phenomena contributing to brain damage. Our previous studies provide evidence for the involvement of the innate immune receptor Toll-like (TLR) 4 in the inflammatory response induced in the frontal cortex and cerebellum in TD animal models (animals fed with TD diet and receiving pyrithiamine). However, the effects of the combination of chronic alcohol consumption and TD on TLR4 and their specific contribution to the pathogenesis of WE are currently unknown. Additionally, no studies on TLR4 have been conducted on WE patients since brains from these patients are difficult to achieve. Here, we used rat models of chronic alcohol (CA; 9 months of forced consumption of 20% (w/v) alcohol), TD hit (TDD; TD diet + daily 0.25 mg/kg i.p. pyrithiamine during 12 days), or a combined treatment (CA+TDD) to check the activation of the proinflammatory TLR4/MyD88 pathway and related markers in the frontal cortex and the cerebellum. In addition, we characterized for the first time the TLR4 and its co-receptor MyD88 signature, along with other markers of this proinflammatory signaling such as phospo-NFkappaB; p65 and IkappaB, in the post-mortem human frontal cortex and cerebellum (gray and white matter) of an alcohol-induced WE patient, comparing it with negative (no disease) and positive (aged brain with Alzheimer disease) control subjects for neuroinflammation. We found an increase in the cortical TLR4 and its adaptor molecule MyD88, together with an upregulation of the proinflammatory signaling molecules p-NFkappaB and IkappaB in the CA+TDD animal model. In the patient diagnosed with alcohol-induced WE we observed cortical and cerebellar upregulation of the TLR4/MyD88 pathway. Thus, our findings provide evidence, both in the animal model and the human postmortem brain, of the upregulation of the TLR4/MyD88 proinflammatory pathway in WE related to alcohol consumption.

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“…TLRs harbor extracellular leucine-rich repeats, a transmembrane domain, and a Toll/IL-1 receptor (TIR) domain, which signal through downstream signaling molecules, such as myeloid differentiation primary response gene 88 (MyD88) and TIR-domain-containing adapter-inducing interferon β (TRIF) ( Figure 1 ) ( Duan et al., 2022 ). Among TLRs, TLR3, TLR7, TLR8, and TLR9 sense NAs ( Majer et al., 2017 ).…”

Section: Na Sensing By Prrsmentioning

confidence: 99%

Pathophysiological Role of Nucleic Acid-Sensing Pattern Recognition Receptors in Inflammatory Diseases

Kano

Ong

Ori

et al. 2022

Front. Cell. Infect. Microbiol.

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Pattern recognition receptors (PRRs) play critical roles in recognizing pathogen-derived nucleic acids and inducing innate immune responses, such as inflammation and type I interferon production. PRRs that recognize nucleic acids include members of endosomal Toll-like receptors, cytosolic retinoic acid inducible gene I-like receptors, cyclic GMP–AMP synthase, absent in melanoma 2-like receptors, and nucleotide binding oligomerization domain-like receptors. Aberrant recognition of self-derived nucleic acids by these PRRs or unexpected activation of downstream signaling pathways results in the constitutive production of type I interferons and inflammatory cytokines, which lead to the development of autoimmune or autoinflammatory diseases. In this review, we focus on the nucleic acid-sensing machinery and its pathophysiological roles in various inflammatory diseases.

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Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity

Cited by 383 publications

References 335 publications

TIRAP/Mal Positively Regulates TLR8-Mediated Signaling via IRF5 in Human Cells

TIRAP/Mal Positively Regulates TLR8-Mediated Signaling via IRF5 in Human Cells

“Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: findings in preclinical models and in a postmortem human case”

Pathophysiological Role of Nucleic Acid-Sensing Pattern Recognition Receptors in Inflammatory Diseases

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