Macrophage-Activating Lipopeptide-2 Requires Mal and PI3K for Efficient Induction of Heme Oxygenase-1

You, Xiaoxing; Liu, Liangzhuan; Zeng, Yanhua; Li, Ranhui; He, Jun; Ma, Xiaotong; Jiang, Chao; Zhu, Chen; Chen, Liesong; Yu, Min; Ou, Guangli; Wu, Yimou

doi:10.1371/journal.pone.0103433

Cited by 7 publications

(7 citation statements)

References 52 publications

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“…Furthermore, Mal is also situated upstream of MyD88 in MALP-2-induced signaling (Santos-Sierra et al, 2009). Moreover, the cytoplasmic adaptor Mal recruits the TLR2/6 heterodimer in response to MALP-2 stimulation (You et al, 2014). Our observations further support the viewpoint that Mal could downregulate the mRNA expression of MyD88 while Mal was somewhat inhibited to different degrees.…”

Section: Discussionsupporting

confidence: 78%

Chlamydia psittaci Plasmid-Encoded CPSIT_P7 Elicits Inflammatory Response in Human Monocytes via TLR4/Mal/MyD88/NF-κB Signaling Pathway

Chen

Yan

et al. 2020

Front. Microbiol.

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The chlamydial plasmid, an essential virulence factor, encodes plasmid proteins that play important roles in chlamydial infection and the corresponding immune response. However, the virulence factors and the molecular mechanisms of Chlamydia psittaci are not well understood. In the present study, we investigated the roles and mechanisms of the plasmid-encoded protein CPSIT_P7 of C. psittaci in regulating the inflammatory response in THP-1 cells (human monocytic leukemia cell line). Based on cytokine arrays, CPSIT_P7 induces the expression of interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1) in THP-1 cells. Moreover, the expression levels of IL-6, IL-8, and MCP-1 stimulated by CPSIT_P7 declined after silencing of the Toll-like receptor 4 (TLR4) gene using small interfering RNA and transfection of a dominant negative plasmid encoding TLR4 (pZERO-hTLR4). We further demonstrated that transfection with the dominant negative plasmid encoding MyD88 (pDeNy-hMyD88) and the dominant negative plasmid encoding Mal (pDeNy-hMal) could also abrogate the expression of the corresponding proteins. Western blot and immunofluorescence assay results showed that CPSIT_P7 could activate nuclear factor κB (NF-κB) signaling pathways in THP-1 cells. Altogether, our results indicate that the CPSIT_P7 induces the TLR4/Mal/MyD88/NF-κB signaling axis and therefore contributes to the inflammatory cytokine response.

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Section: Discussionsupporting

confidence: 78%

Chlamydia psittaci Plasmid-Encoded CPSIT_P7 Elicits Inflammatory Response in Human Monocytes via TLR4/Mal/MyD88/NF-κB Signaling Pathway

Chen

Yan

et al. 2020

Front. Microbiol.

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“…Nrf2 activates a series of downstream phase II detoxification and antioxidant enzymes upon exposure to oxidative stressors [ 57 ]. HO-1 is an antioxidant enzyme with antioxidant-based cytoprotective effects [ 58 , 59 ], whose gene expression is mediated through an Nrf2-activated redox-dependent signaling pathway, and it is involved in the activation of Btk [ 18 , 60 ]. TLR agonists may act as activators of the Nrf2 pathway, promoting the expression of antioxidant molecules [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Lactobacillus delbrueckii Protected Intestinal Integrity, Alleviated Intestinal Oxidative Damage, and Activated Toll-Like Receptor–Bruton’s Tyrosine Kinase–Nuclear Factor Erythroid 2-Related Factor 2 Pathway in Weaned Piglets Challenged with Lipopolysaccharide

Chen

et al. 2021

Antioxidants

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Oxidative stress is increasingly being recognized as a player in the pathogenesis of intestinal pathologies, and probiotics are becoming an attractive means of addressing it. The present study investigated the effects of dietary supplementation with Lactobacillus delbrueckii (LAB) on intestinal integrity and oxidative damage in lipopolysaccharide (LPS)-challenged piglets. A total of 36 crossbred weaned piglets (Duroc × Landrace × Large Yorkshire) were randomly divided into three groups: (1) non-challenged controls (CON), (2) LPS-challenged controls (LPS), and (3) 0.2% LAB (2.01 × 1010 CFU/g) + LPS treatment (LAB + LPS). On the 29th day of the experiment, the LPS and CON groups were injected intraperitoneally with LPS and saline at 100 ug/kg body weight, respectively. The results show that the LPS-induced elevation of the serum diamine oxidase (DAO) level and small intestinal crypt depth (CD) were reversed by the dietary addition of LAB, which also markedly increased the ileal expression of tight junction proteins (occludin, ZO-1, and claudin-1) in the LPS-challenged piglets. Furthermore, LAB supplementation normalized other LPS-induced changes, such as by decreasing malondialdehyde (MDA) in both the serum and intestinal mucosa and 8-hydroxy-2-deoxyguanosine (8-OHdG) in the jejunal mucosa, increasing glutathione reductase (GR) and glutathione peroxidase (GSH-Px) in both the serum and intestinal mucosa, and increasing glutathione (GSH) and superoxide dismutase (SOD) in the jejunal mucosa. LAB also activated Toll-like receptor (TLR)–Bruton’s tyrosine kinase (Btk)–nuclear factor erythroid 2-related factor 2(Nrf2) signaling pathways in the intestine, suggesting that it plays a vital role in the ameliorative antioxidant capacity of weaned piglets. In summary, LAB increased intestinal integrity by improving the intestinal structure and tight junctions while enhancing antioxidant functions via the activation of the TLR–Btk–Nrf2 signaling pathway.

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“…The interaction of p85α, a regulatory subunit of phosphoinositide 3-kinase (PI3K) with TIRAP, is a MyD88-independent response of the TLR2 receptor upon stimulation with bacterial lipoproteins ( 16 , 21 ). This interaction is highly significant in TLR2 and TLR6 heterodimer signaling, resulting in the activation of PI3K-dependent phosphorylation of Akt, PIP 3 [phosphatidylinositol (3,4,5)P 3 ] generation, and polar shape changes of the macrophage ( 16 ).…”

Section: Tirap and Phosphatidylinositol 3′-kinase P85 And B-cell Adaptor For Phosphoinositide 3-kinase (Bcap)mentioning

confidence: 99%

“…MALP-2 induced activation of the TLR2/6 pathway in THP-1 cells also induces the interaction of TIRAP with p85α, and this is essential for the induction of Heme Oxygenase-1 (HO-1) via Akt phosphorylation and Nrf2 activation ( 21 ). Similar to the above study, this study also reported that MyD88 deficiency resulted in decreased Akt phosphorylation but at earlier time points post-activation (60 minutes).…”

Section: Tirap and Phosphatidylinositol 3′-kinase P85 And B-cell Adaptor For Phosphoinositide 3-kinase (Bcap)mentioning

confidence: 99%

TIRAP in the Mechanism of Inflammation

et al. 2021

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The Toll-interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP) represents a key intracellular signalling molecule regulating diverse immune responses. Its capacity to function as an adaptor molecule has been widely investigated in relation to Toll-like Receptor (TLR)-mediated innate immune signalling. Since the discovery of TIRAP in 2001, initial studies were mainly focused on its role as an adaptor protein that couples Myeloid differentiation factor 88 (MyD88) with TLRs, to activate MyD88-dependent TLRs signalling. Subsequent studies delineated TIRAP’s role as a transducer of signalling events through its interaction with non-TLR signalling mediators. Indeed, the ability of TIRAP to interact with an array of intracellular signalling mediators suggests its central role in various immune responses. Therefore, continued studies that elucidate the molecular basis of various TIRAP-protein interactions and how they affect the signalling magnitude, should provide key information on the inflammatory disease mechanisms. This review summarizes the TIRAP recruitment to activated receptors and discusses the mechanism of interactions in relation to the signalling that precede acute and chronic inflammatory diseases. Furthermore, we highlighted the significance of TIRAP-TIR domain containing binding sites for several intracellular inflammatory signalling molecules. Collectively, we discuss the importance of the TIR domain in TIRAP as a key interface involved in protein interactions which could hence serve as a therapeutic target to dampen the extent of acute and chronic inflammatory conditions.

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Macrophage-Activating Lipopeptide-2 Requires Mal and PI3K for Efficient Induction of Heme Oxygenase-1

Cited by 7 publications

References 52 publications

Chlamydia psittaci Plasmid-Encoded CPSIT_P7 Elicits Inflammatory Response in Human Monocytes via TLR4/Mal/MyD88/NF-κB Signaling Pathway

Chlamydia psittaci Plasmid-Encoded CPSIT_P7 Elicits Inflammatory Response in Human Monocytes via TLR4/Mal/MyD88/NF-κB Signaling Pathway

Lactobacillus delbrueckii Protected Intestinal Integrity, Alleviated Intestinal Oxidative Damage, and Activated Toll-Like Receptor–Bruton’s Tyrosine Kinase–Nuclear Factor Erythroid 2-Related Factor 2 Pathway in Weaned Piglets Challenged with Lipopolysaccharide

TIRAP in the Mechanism of Inflammation

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