The effects of CD14 and IL-27 on induction of endotoxin tolerance in human monocytes and macrophages

Petes, Carlene; Mintsopoulos, Victoria; Finnen, Renée L.; Banfield, Bruce W.; Gee, Katrina

doi:10.1074/jbc.ra118.003501

Cited by 19 publications

(13 citation statements)

References 94 publications

(93 reference statements)

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“…While TLR4 and MD2 were expressed at similar levels in both cell lines, CD14 expression was 4-fold lower in THP-1 vs . 786-O cells, as judged by FACS analysis ( S2B Fig ), in good agreement with a previous report [ 32 ]. The expression of the TLR4 canonical adaptor MyD88 was similar in both cell lines ( S2A Fig ).…”

Section: Resultssupporting

confidence: 92%

“…We first assessed protein expression levels of the main components of the LPS recognition complex (i.e., TLR4, MD2, MyD88 and CD14) by Western blotting and/or flow cytometry (S2 Fig). While TLR4 and MD2 were expressed at similar levels in both cell lines, CD14 expression was 4-fold lower in THP-1 vs. 786-O cells, as judged by FACS analysis (S2B Fig), in good agreement with a previous report [32]. The expression of the TLR4 canonical adaptor MyD88 was similar in both cell lines (S2A Fig).…”

Section: Only Potent Tlr4-activating Endotoxins Can Potentiate the Prsupporting

confidence: 90%

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Toll-like receptor 4-mediated inflammation triggered by extracellular IFI16 is enhanced by lipopolysaccharide binding

et al. 2020

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Damage-associated molecular patterns (DAMPs) are endogenous molecules activating the immune system upon release from injured cells. Here we show that the IFI16 protein, once freely released in the extracellular milieu of chronically inflamed tissues, can function as a DAMP either alone or upon binding to lipopolysaccharide (LPS). Specifically, using pulldown and saturation binding experiments, we show that IFI16 binds with high affinity to the lipid A moiety of LPS. Remarkably, IFI16 DAMP activity is potentiated upon binding to subtoxic concentrations of strong TLR4-activating LPS variants, as judged by TLR4-MD2/ TIRAP/MyD88-dependent IL-6, IL-8 and TNF-α transcriptional activation and release in stimulated monocytes and renal cells. Consistently, using co-immunoprecipitation (co-IP) and surface plasmon resonance (SPR) approaches, we show that IFI16 is a specific TLR4ligand and that IFI16/LPS complexes display a faster stimulation turnover on TLR4 than LPS alone. Altogether, our findings point to a novel pathomechanism of inflammation involving the formation of multiple complexes between extracellular IFI16 and subtoxic doses of LPS variants, which then signal through TLR4.

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Section: Resultssupporting

confidence: 92%

Section: Only Potent Tlr4-activating Endotoxins Can Potentiate the Prsupporting

confidence: 90%

Toll-like receptor 4-mediated inflammation triggered by extracellular IFI16 is enhanced by lipopolysaccharide binding

et al. 2020

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“…To investigate TLR2 signaling in human myeloid cells, we employed the human acute monocytic leukemia-derived cell line THP1, which is highly manipulable and widely used for deciphering mechanistic aspects of (innate) immune signaling (38,39). THP1 cells have a monocyte-like phenotype and can be differentiated towards macrophage-like cells using the phorbol ester PMA (40).…”

Section: Human Monocytes But Not Macrophages Support Tlr2-dependentmentioning

confidence: 99%

An alternative model for type I interferon induction downstream of human TLR2

Oosenbrug

Graaff

Haks

et al. 2020

Journal of Biological Chemistry

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Surface-exposed Toll-like receptors (TLRs) such as TLR2 and TLR4 survey the extracellular environment for pathogens. TLR activation initiates the production of various cytokines and chemokines including type I interferons (IFN-I). Downstream of TLR4, IFNβ secretion is only vigorously triggered in macrophages when the receptor undergoes endocytosis and switches signaling adaptor; surface TLR4 engagement predominantly induces proinflammatory cytokines via the signaling adaptor MyD88. It is unclear if this dichotomy is generally applicable to other TLRs, cell types, or differentiation states. Here, we report that diverse TLR2 ligands induce an IFN-I response in human monocyte-like cells, but not in differentiated macrophages. This TLR2-dependent IFN-I signaling originates from the cell surface and is dependent on MyD88; it involves combined activation of the transcription factors IRF3 and NF-κB, driven by the kinases TBK1 and TAK1-IKKβ, respectively. TLR2-stimulated monocytes produced modest IFNβ levels that caused productive downstream signaling, reflected by STAT1-phosphorylation and expression of numerous interferon-stimulated genes (ISGs). Our findings reveal that the outcome of TLR2 signaling includes an IFN-I response in human monocytes, which is lost upon macrophage differentiation, and differs mechanistically from IFN-I-induction through TLR4. These findings point to molecular mechanisms tailored to the differentiation state of a cell and the nature of receptors activated to control and limit TLR-triggered IFN-I responses.

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“…Nevertheless, we identify novel alterations to the expression of CD64 on classical monocytes and CD14 across all monocyte subsets. Enhanced CD14 expression on monocytes has been linked to the acquisition of a tolerance to endotoxin exposure, characterized by an inability to secrete proinflammatory cytokines [62], a phenotype observed in stroke [92]. However, it is unclear if the increased levels of CD14 on monocytes are driven by up-regulation or the generation and release of CD14 high monocytes from the bone marrow, analogous to the concept of innate immune training [15,93,94].…”

Section: Discussionmentioning

confidence: 99%

A hyperacute immune map of ischaemic stroke patients reveals alterations to circulating innate and adaptive cells

Krishnan

O’Boyle

Smith

et al. 2020

Clinical and Experimental Immunology

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Stroke affects millions of people across the globe and infections following a stroke often lead to death or disability in patients. Looking rapidly after a stroke in patients, we identify early alterations to the innate and adaptive cells in circulation. Our findings highlight novel changes to dendritic cells, monocytes, haematopoietic stem and progenitor cells, B and T cells to be further investigated as they could have implications the development of post‐stroke infection and poorer patient outcomes.

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The effects of CD14 and IL-27 on induction of endotoxin tolerance in human monocytes and macrophages

Cited by 19 publications

References 94 publications

Toll-like receptor 4-mediated inflammation triggered by extracellular IFI16 is enhanced by lipopolysaccharide binding

Toll-like receptor 4-mediated inflammation triggered by extracellular IFI16 is enhanced by lipopolysaccharide binding

An alternative model for type I interferon induction downstream of human TLR2

A hyperacute immune map of ischaemic stroke patients reveals alterations to circulating innate and adaptive cells

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