Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis

Thada, Shruthi; Horváth, Gábor; Mm, Müller; Dittrich, Nickel; Conrad, Melanie L.; Sur, Saubashya; Hussain, Abid; Pelka, Karin; Gaddam, Sumanlatha; Latz, Eicke; Slevogt, Hortense; Schumann, Ralf R.; Burkert, Sanne

doi:10.3390/ijms22041560

Cited by 19 publications

(14 citation statements)

References 59 publications

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“…The relationship between IRF3 and TLRs has been well documented with several studies reporting an interaction between TLR4/TRIF/IRF3 signaling 44–46 . IRF3 has been implemented in the development of insulin resistance and suggested as a possible therapeutic target 22 .…”

Section: Discussionmentioning

confidence: 99%

“…The relationship between IRF3 and TLRs has been well documented with several studies reporting an interaction between TLR4/TRIF/IRF3 signaling. 44 , 45 , 46 IRF3 has been implemented in the development of insulin resistance and suggested as a possible therapeutic target. 22 The manipulation of TLRs that lay upstream of IRF3 was found to influence insulin resistance in murine adipocytes whereas the knockdown of IRF3 abolished insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

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TLR13 contributes to skeletal muscle atrophy by increasing insulin resistance in chronic kidney disease

Wang

Zhang

et al. 2022

Cell Proliferation

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Objectives Insulin resistance in chronic kidney disease (CKD) stimulates muscle wasting, but the molecular processes behind the resistance are undetermined. However, inflammation in skeletal muscle is implicated in the pathogenesis of insulin resistance and cachexia. Toll‐like receptors (TLRs) are known to regulate local innate immune responses, and microarray data have shown that Tlr13 is upregulated in the muscles of mice with CKD, but the relevance is unknown. Materials and Methods We performed in vitro experiments in C2C12 myotubes and constructed a CKD murine model using subtotal nephrectomy to conduct experiments in vivo. Results Tlr13 expression was stimulated in C2C12 myotubes treated with uremic serum. The expression of Tlr13 was also upregulated in the tibialis anterior muscles of mice with CKD. Tlr13 knockdown with siRNAs in skeletal muscle cells decreased insulin resistance despite the inclusion of uremic serum. This led to increased levels of p‐AKT and suppression of protein degradation. Using immunofluorescence staining and coimmunoprecipitation assay, we found that TLR13 recruits IRF3, which activates Irf3 expression, resulting in decreased AKT activity. Moreover, insulin resistance and proteolysis are re‐induced by Irf3 overexpression under Tlr13 deletion. Conclusions Our results indicate that TLR13 is involved in CKD‐mediated insulin resistance in muscle. In catabolic conditions where insulin signaling is impaired, targeting TLR13 may improve insulin sensitivity and prevent muscle atrophy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TLR13 contributes to skeletal muscle atrophy by increasing insulin resistance in chronic kidney disease

Wang

Zhang

et al. 2022

Cell Proliferation

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“…Cell-type specific differences in the expression level and utilization of TIRAP in TLR8 signaling should also be addressed. Furthermore, SNPs in TIRAP are associated to the incidence and severity of several diseases, such as tuberculosis, HIV, and systemic lupus erythematosus (SLE) [ 18 ] as well as infections/diseases in which TLR8 is likely to play a role [ 63 , 64 , 65 ]. Thus, understanding the contribution of TIRAP to the fine-tuning of TLR8 signaling might be of significant clinical relevance.…”

Section: Discussionmentioning

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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“…Immune cells can be activated by the interaction between TLR4 and Mtb components, such as secretory protein (Rv0335c), lipomannan (LM), HSPs 60, and 65 [ 65 , 102 ]. In a recent study, Thada et al found that TLR4 can bind TLR8 to recognize TLR8 ligands produced by Mtb [ 103 ]. In chronic Mtb infection, it has been demonstrated that macrophage recruitment, pro-inflammatory responses, and the ability to eliminate mycobacteria were impaired in TLR4 deficient mice [ 104 ].…”

Section: Tlr2 Function In Immune Responses To Mycobacterial Infectionmentioning

confidence: 99%

The Role of TLR2 in Infectious Diseases Caused by Mycobacteria: From Cell Biology to Therapeutic Target

Spaink

2022

Biology

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Innate immunity is considered the first line of defense against microbial invasion, and its dysregulation can increase the susceptibility of hosts to infections by invading pathogens. Host cells rely on pattern recognition receptors (PRRs) to recognize invading pathogens and initiate protective innate immune responses. Toll-like receptor 2 (TLR2) is believed to be among the most important Toll-like receptors for defense against mycobacterial infection. TLR2 has been reported to have very broad functions in infectious diseases and also in other diseases, such as chronic and acute inflammatory diseases, cancers, and even metabolic disorders. However, TLR2 has an unclear dual role in both the activation and suppression of innate immune responses. Moreover, in some studies, the function of TLR2 was shown to be controversial, and therefore its role in several diseases is still inconclusive. Therefore, although TLR2 has been shown to have an important function in innate immunity, its usefulness as a therapeutic target in clinical application is still uncertain. In this literature review, we summarize the knowledge of the functions of TLR2 in host–mycobacterial interactions, discuss controversial results, and suggest possibilities for future research.

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Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis

Cited by 19 publications

References 59 publications

TLR13 contributes to skeletal muscle atrophy by increasing insulin resistance in chronic kidney disease

TLR13 contributes to skeletal muscle atrophy by increasing insulin resistance in chronic kidney disease

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

The Role of TLR2 in Infectious Diseases Caused by Mycobacteria: From Cell Biology to Therapeutic Target

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