Targeting the Toll-like Receptor/Interleukin 1 Receptor Pathway in Human Diseases: Rational Design of MyD88 Inhibitors

Loiarro, Maria; Ruggiero, Vito; Sette, Claudio

doi:10.1016/j.clml.2013.02.003

Cited by 24 publications

(21 citation statements)

References 24 publications

(30 reference statements)

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“…Our results suggest that impairment of lysosomes, especially of lysosomal aspartic proteases, causes MyD88 accumulation that triggers such initial inflammatory signals. MyD88-mediated signaling has been actually shown to be important for the production of pro-IL-1β and pro-IL-18 3, 41 . It is also known that MyD88-mediated signaling incidentally exacerbates inflammatory conditions, and its excessive or prolonged induction leads to chronic inflammation associated with autoimmunity and autoinflammation 42, 43 .…”

Section: Discussionmentioning

confidence: 99%

Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88

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Horie

Inomata

et al. 2017

Sci Rep

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Autophagy, the processes of delivery of intracellular components to lysosomes, regulates induction of inflammation. Inducible macroautophagy degrades inflammasomes and dysfunctional mitochondria to downregulate inflammatory signals. Nonetheless, the effects of constitutive basal autophagy on inflammatory signals are largely unknown. Here, we report a previously unknown effect of basal autophagy. Lysosomal inhibition induced weak inflammatory signals in the absence of a cellular stimulus and in the presence of a nutrient supply, and their induction was impaired by MyD88 deficiency. During lysosomal inhibition, MyD88 was accumulated, and overabundant MyD88 autoactivated downstream signaling or enhanced TLR/IL-1R-mediated signaling. MyD88 is probably degraded via basal microautophagy because macroautophagy inhibitors, ATG5 deficiency, and an activator of chaperone-mediated autophagy did not affect MyD88. Analysis using a chimeric protein whose monomerization/dimerization can be switched revealed that monomeric MyD88 is susceptible to degradation. Immunoprecipitation of monomeric MyD88 revealed its interaction with TRAF6. In TRAF6-deficient cells, degradation of basal MyD88 was enhanced, suggesting that TRAF6 participates in protection from basal autophagy. Thus, basal autophagy lowers monomeric MyD88 expression, and thereby autoactivation of inflammatory signals is prevented. Given that impairment of lysosomes occurs in various settings, our results provide novel insights into the etiology of inflammatory signals that affect consequences of inflammation.

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Section: Discussionmentioning

confidence: 99%

Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88

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Horie

Inomata

et al. 2017

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“…This drug inhibits LPS-induced production of inflammatory cytokines, MAP kinases and NF-κB activation by a mechanism related to inhibition of Src- and Syk-mediated PI3K- (p85) tyrosine phosphorylation and subsequent TLR4/MyD88/PI 3 K complex formation, which limits the activation of downstream signaling pathways [17]. Cell-permeable peptides and peptidomimetic agents are being developed that selectively inhibit MyD88 homodimerization and function [35]. Regarding TLR4/TRIF signaling, LPS treatment reduces H5N1 influenza virus replication and lethality in a TRIF-dependent manner [36].…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide Induces Inflammatory Hyperalgesia Triggering a TLR4/MyD88-Dependent Cytokine Cascade in the Mice Paw

et al. 2014

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Inflammatory pain can be triggered by different stimuli, such as trauma, radiation, antigen and infection. In a model of inflammatory pain caused by infection, injection in the mice paw of lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) agonist, produces mechanical hyperalgesia. We identify here the TLR4 linked signaling pathways that elicit this response. Firstly, LPS paw injection in wild type (WT) mice produced mechanical hyperalgesia that was not altered in TRIF-/- mice. On the other hand, this response was absent in TLR4 mutant and MyD88 null mice and reduced in TNFR1 null mice. Either an IL-1 receptor antagonist, anti-KC/CXCL1 antibody, indomethacin or guanethidine injection also lessened this response. Moreover, LPS-induced time dependent increases in TNF-α, KC/CXCL1 and IL-1β expression in the mice paw, which were absent in TLR4 mutant and MyD88 null mice. Furthermore, in TNFR1 deficient mice, the LPS-induced rises in KC/CXCL1 and IL-1β release were less than in their wild type counterpart. LPS also induced increase of myeloperoxidase activity in the paw skin, which was inhibited in TLR4 mutant and MyD88 null mice, and not altered in TRIF-/- mice. These results suggest that LPS-induced inflammatory pain in mice is solely dependent on the TLR4/MyD88 rather than the TLR4/TRIF signaling pathway. This pathway triggers pronociceptive cytokine TNF-α release that in turn mediates rises in KC/CXCL1 and IL-1β expression. Finally, these cytokines might be involved in stimulating production of directly-acting hyperalgesic mediators such as prostaglandins and sympathomimetic amine.

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“…Due to its activating effect on NF-κB signaling through the Toll-like receptor/interleukin 1 pathway, MYD88 mutation status is likely to be of interest for upcoming targeted therapy approaches [7]. …”

Section: Tablementioning

confidence: 99%

Oncogenic <b><i>MYD88</i></b> Mutations Are Rare Events in Double-Hit B-Cell Lymphomas

Gebauer

Bernard²,

Thorns³

et al. 2014

Acta Haematol

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Targeting the Toll-like Receptor/Interleukin 1 Receptor Pathway in Human Diseases: Rational Design of MyD88 Inhibitors

Cited by 24 publications

References 24 publications

Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88

Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88

Lipopolysaccharide Induces Inflammatory Hyperalgesia Triggering a TLR4/MyD88-Dependent Cytokine Cascade in the Mice Paw

Oncogenic <b><i>MYD88</i></b> Mutations Are Rare Events in Double-Hit B-Cell Lymphomas

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