A universal role for MyD88 in TLR/IL-1R-mediated signaling

Janssens, Sophie; Beyaert, Rudi

doi:10.1016/s0968-0004(02)02145-x

Cited by 360 publications

(284 citation statements)

References 55 publications

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“…As stated above, MyD88 is one of the five TIR domaincontaining adaptors in TLR signaling (112) and plays a critical role in the signaling of all TLRs except TLR3 (64,104,108) (Fig. 1).…”

Section: Tlr-signaling Pathwaysmentioning

confidence: 88%

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

Chao¹

2009

American Journal of Physiology-Heart and Circulatory Physiology

209

165

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Toll-like receptors (TLRs) represent the first line of host defense against microbial infection and play a pivotal role in both innate and adaptive immunity. TLRs recognize invading pathogens through molecular pattern recognition, transduce signals via distinct intracellular pathways involving a unique set of adaptor proteins and kinases, and ultimately lead to the activation of transcription factors and inflammatory responses. Among 10 TLRs identified in humans, at least two exist in the heart, i.e., TLR2 and TLR4. In addition to the critical role of these in mediating cardiac dysfunction in septic conditions, emerging evidence suggests that the TLRs can also recognize endogenous ligands and may play an important role in modulating cardiomyocyte survival and in ischemic myocardial injury. In animal models of ischemia-reperfusion injury or in hypoxic cardiomyocytes in vitro, the administration of a sublethal dose of lipopolysaccharide, which signals through TLR4, reduces subsequent myocardial infarction, improves cardiac functions, and attenuates cardiomyocyte apoptosis. By contrast, a systemic deficiency of TLR2, TLR4, or myeloid differentiation primary-response gene 88, an adaptor critical for all TLR signaling, except TLR3, leads to an attenuated myocardial inflammation, a smaller infarction size, a better preserved ventricular function, and a reduced ventricular remodeling after ischemic injury. These loss-of-function studies suggest that both TLRs contribute to myocardial inflammation and ischemic injury in the heart although the exact contribution of cardiac (vs. circulatory cell) TLRs remains to be defined. These recent studies demonstrate an emerging role for TLRs as a critical modulator in both cell survival and tissue injury in the heart.

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“…As stated above, MyD88 is one of the five TIR domaincontaining adaptors in TLR signaling (112) and plays a critical role in the signaling of all TLRs except TLR3 (64,104,108) (Fig. 1).…”

Section: Tlr-signaling Pathwaysmentioning

confidence: 88%

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

Chao¹

2009

American Journal of Physiology-Heart and Circulatory Physiology

209

165

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“…Limitations of this study include the fact that that we did not assess whether MSU crystals regulate inflammation indirectly through TLR and MyD88 signaling via induced cellular release of endogenous ligands of TLR-2 and TLR-4, such as Hsp70 and HMGB-1 (51,52). MyD88 is one of several cytosolic adapter proteins for TLR-2 and TLR-4 (26), and MyD88 also transduces IL-1R-mediated responses (53). These are points to be considered because we did not test to determine whether the blunting effects of MyD88 deficiency on MSU crystal-induced macrophage activation and inflammation were mediated partly by impaired IL-1 signaling.…”

Section: Discussionmentioning

confidence: 99%

Innate immunity conferred by toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation

et al. 2005

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Objective. In gout, incompletely defined molecular factors alter recognition of dormant articular and bursal monosodium urate monohydrate (MSU) crystal deposits, thereby inducing self-limiting bouts of characteristically severe neutrophilic inflammation. To define primary determinants of cellular recognition, uptake, and inflammatory responses to MSU crystals, we conducted a study to test the role of Toll-like receptor 2 (TLR-2), TLR-4, and the cytosolic TLR adapter protein myeloid differentiation factor 88 (MyD88), which are centrally involved in innate immune recognition of microbial pathogens.Methods. We isolated bone marrow-derived macrophages (BMDMs) in TLR-2 ؊/؊ , TLR-4 ؊/؊ , MyD88 ؊/؊ , and congenic wild-type mice, and assessed phagocytosis and cytokine expression in response to endotoxin-free MSU crystals under serum-free conditions. MSU crystals also were injected into mouse synovium-like subcutaneous air pouches.Results. TLR-2 ؊/؊ , TLR-4 ؊/؊ , and MyD88 ؊/؊ BMDMs demonstrated impaired uptake of MSU crystals in vitro. MSU crystal-induced production of interleukin-1␤ (IL-1␤), tumor necrosis factor ␣, keratinocyte-derived cytokine/growth-related oncogene ␣, and transforming growth factor ␤1 also were significantly suppressed in TLR-2 ؊/؊ and TLR-4 ؊/؊ BMDMs and were blunted in MyD88 ؊/؊ BMDMs in vitro. Neutrophil influx and local induction of IL-1␤ in subcutaneous air pouches were suppressed 6 hours after injection of MSU crystals in TLR-2 ؊/؊ and TLR-4 ؊/؊ mice and were attenuated in MyD88 ؊/؊ mice.Conclusion. The murine host requires TLR-2, TLR-4, and MyD88 for macrophage activation and development of full-blown neutrophilic, air pouch inflammation in response to MSU crystals. Our findings implicate innate immune cellular recognition of naked MSU crystals by specific TLRs as a major factor in determining the inflammatory potential of MSU crystal deposits and the course of gouty arthritis.

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“…The conserved role of MyD88 in TLR signaling transduction has been confirmed ranging from mammals to mollusks, including human [14], rat [4], Xenopus [15], fish [16], Drosophila [17], Chlamys farreri [18],etc. Unexpectedly, we found two novel truncated forms of Myd88 lacking DD domain, CgMyD88-T1 and CgMyD88-T2.…”

Section: Discussionmentioning

confidence: 96%

“…Once bound with PAMPs, the intracellular TIR domain of TLRs would recruit several downstream signaling adaptors through TIR dimerization and activate nuclear factor-kB(NF-kB) consequently [2]. Among these adaptors, MyD88 is one of the curial and conserved signaling proteins that mediates activation of most of all TLRs except forTLR3 [3,4]. In the mammals, the typical Myd88 contains three domains, including the N-terminal death domain (DD), one short intermediate domain (ID) and the C-terminal TIR domain [5].…”

Section: Introductionmentioning

confidence: 99%

“…In the mammals, the typical Myd88 contains three domains, including the N-terminal death domain (DD), one short intermediate domain (ID) and the C-terminal TIR domain [5]. Through the DD, MyD88, IRAK4 can be recruited and phosphorylated, leading to the activation of TRAF6-TAK1-NF-kB signaling pathway and induction of various inflammatory cytokines [4].…”

Section: Introductionmentioning

confidence: 99%

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Expression and function analysis of two naturally truncated MyD88 variants in the Pacific oyster Crassostrea gigas

Xu¹,

Zhang²,

Li³

et al. 2015

Fish & Shellfish Immunology

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A universal role for MyD88 in TLR/IL-1R-mediated signaling

Cited by 360 publications

References 55 publications

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

Innate immunity conferred by toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation

Expression and function analysis of two naturally truncated MyD88 variants in the Pacific oyster Crassostrea gigas

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