Myeloid Differentiation Primary Response Protein 88 (MyD88): The Central Hub of TLR/IL-1R Signaling

Chen, Lingfeng; Zheng, Lulu; Chen, Pengqin; Liang, Guang

doi:10.1021/acs.jmedchem.0c00884

Cited by 81 publications

(53 citation statements)

References 146 publications

(262 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The activated TAK1 complex activates IKK through phosphorylation. Activated IKK phosphorylates the inhibitor protein of NF-κB (IκBα), which releases NF-κB and translocates into the nucleus, inducing increased expression of a series of inflammatory factors [ 32 ]. As an another key downstream signaling pathways of IRAK4, p38 signaling pathways involved in the synthesis of articular cartilage matrix metalloproteinases, the production of inflammatory cytokines, maintain and differentiation in the phenotype of chondrocytes, hypertrophy and calcification of chondrocytes, closely related to the apoptosis of chondrocytes, plays a crucial role in the process of articular cartilage degeneration [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model

Ran

et al. 2021

Arthritis Res Ther

View full text Add to dashboard Cite

Background The use of interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor as a treatment for the inflammatory joint disease is a promising method. However, its underlying mechanism in osteoarthritis (OA) remains unclear. The purpose of this study is to look into the effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the OA rabbit model. Methods Ad-shIRAK4 was injected two weeks after anterior cruciate ligament resection. Six weeks later, the rabbits were killed. The expression of IRAK4, TNFR-associated factor 6(TRAF6), TGF-activated kinase 1(TAK1), p-IKB kinase (p-IKK), p-nuclear factor kappa-B (p-NFκB), p38, and p-p38 in the synovial membrane was detected by western blot, qRT-PCR, and immunohistochemistry analysis. Immunohistochemistry was to detect the expression of IRAK4 proteins in articular cartilage. H&E staining was to assess the pathological changes of synovium and cartilage. The levels of interleukin (IL)-1β, tumor necrosis factor-α(TNF-α), and MMP-13 in the synovial fluid were measured by ELISA. X-ray and micro-computerized tomography (μCT) scans were used to assess knee joint conditions and microstructure of subchondral bone. Results IRAK4 expression levels in synovial tissues of the OA model group exhibited a significant upward trend. Ad-shIRAK4 significantly reduced IRAK4 mRNA expression in synovium tissues. Notably, Ad-shIRAK4 suppressed the Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) signaling. In addition, in the Ad-shIRAK4 treatment group, we can see less inflammatory cell infiltration and reduced hyperplasia and angiogenesis. The levels of IL-1β, TNF-α, and MMP-13 in the synovial fluid in the OA model group were significantly higher than that in the control group, which were reduced by Ad-shIRAK4 treatment. Finally, Results of HE stains, immunohistochemistry, and μCT showed that Ad-shIRAK4 treatment has a protective effect on cartilage damage. Conclusions IRAK4 is significantly upregulated in the synovium from the osteoarthritis rabbit model. In addition, Ad-shIRAK4 reduced the expression of IRAK4 and suppressed TLR/IL-1R signaling in the synovium from the osteoarthritis rabbit model. Ad-shIRAK4 could alleviate synovitis and cartilage degradation in the osteoarthritis rabbit model, and thus alleviate the symptoms of OA and prevent the progression of OA. Graphical abstract

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model

Ran

et al. 2021

Arthritis Res Ther

View full text Add to dashboard Cite

show abstract

“…Myeloid differentiation primary response protein 88 (MYD88) is mainly located in the plasma and acts as an key adaptor protein in the downstream of toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways. TLRs are the superfamily of pattern recognition receptors that activate and mediate innate and adaptive immunity (18,19). They participate in the tumor-related immunity responses contributing to the development and progression of tumors (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

“…MYD88 protein is a commonly expressed adaptor protein in the cytoplasm (35). It plays a key role in the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways responding to the pathogenassociated molecular patterns (PAMPs) produced by infectious microbes and damage-associated molecular pattern molecules (DAMPs) derived from injured host cells (18). TLRs belong to type I transmembrane proteins, including an N-terminal, leucine-rich repeat domain, a single transmembrane link, and a C-terminal cytoplasmic domain (36).…”

mentioning

confidence: 99%

MYD88 Is a Potential Prognostic Gene and Immune Signature of Tumor Microenvironment for Gliomas

2021

View full text Add to dashboard Cite

PurposeTo explore the profiles of immune and stromal components of the tumor microenvironment (TME) and their related key genes in gliomas.MethodsWe applied bioinformatic techniques to identify the core gene that participated in the regulation of the TME of the gliomas. And immunohistochemistry staining was used to calculate the gene expressions in clinical cases.ResultsThe CIBERSORT and ESTIMATE were used to figure out the composition of TME in 698 glioma cases from The Cancer Genome Atlas (TCGA) database. Differential expression analysis identified 2103 genes between the high and the low-score group. Then the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, univariate Cox regression analysis, and protein–protein interaction (PPI) network construction were conducted based on these genes. MYD88 was identified as the key gene by the combination univariate Cox and PPI analysis. Furthermore, MYD88 expression was significantly associated with the overall survival and WHO grade of glioma patients. The genes in the high-expression MYD88 group were mainly in immune-related pathways in the Gene Set Enrichment Analysis (GSEA). We found that macrophage M2 accounted for the largest portion with an average of 27.6% in the glioma TIICs and was associated with high expression of MYD88. The results were verified in CGGA database and clinical cases in our hospital. Furthermore, we also found the MYD88 expression was higher in IDH1 wild types. The methylation rate was lower in high grade gliomas.ConclusionMYD88 had predictive prognostic value in glioma patients by influencing TIICs dysregulation especially the M2-type macrophages.

show abstract

“…MyD88 is a 33-kDa protein containing an N-terminal death domain and a C-terminal Toll/interleukin-1 receptor (TIR) domain, which are separated by a short intermediate domain ( Chen et al, 2020 ). Meantime, it is also the hub protein of the TLR signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel MyD88 Inhibitor M20 and Its Protection Against Sepsis-Mediated Acute Lung Injury

et al. 2021

View full text Add to dashboard Cite

Myeloid differentiation factor 88 (MyD88) is a hub protein in the Toll-like receptor signaling pathway, which acts as a master switch for numerous inflammatory diseases, including acute lung injury (ALI). Although this protein is considered as a crucial therapeutic target, there are currently no clinically approved MyD88-targeting drugs. Based on previous literature, here we report the discovery via computer-aided drug design (CADD) of a small molecule, M20, which functions as a novel MyD88 inhibitor to efficiently relieve lipopolysaccharide-induced inflammation both in vitro and in vivo. Computational chemistry, surface plasmon resonance detection (SPR) and biological experiments demonstrated that M20 forms an important interaction with the MyD88-Toll/interleukin-1 receptor domain and thereby inhibits the protein dimerization. Taken together, this study found a MyD88 inhibitor, M20, with a novel skeleton, which provides a crucial understanding in the development and modification of MyD88 inhibitors. Meanwhile, the favorable bioactivity of the hit compound is also conducive to the treatment of acute lung injury or other more inflammatory diseases.

show abstract

Myeloid Differentiation Primary Response Protein 88 (MyD88): The Central Hub of TLR/IL-1R Signaling

Cited by 81 publications

References 146 publications

Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model

Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model

MYD88 Is a Potential Prognostic Gene and Immune Signature of Tumor Microenvironment for Gliomas

Discovery of a Novel MyD88 Inhibitor M20 and Its Protection Against Sepsis-Mediated Acute Lung Injury

Contact Info

Product

Resources

About