LPS response and endotoxin tolerance in Flt-3L-induced bone marrow-derived dendritic cells

Patenaude, Johane; D’Elia, Michele; Côté-Maurais, Guillaume; Bernier, Jacques

doi:10.1016/j.cellimm.2011.06.020

Cited by 13 publications

(18 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with other studies15, 35, 53 we observed a 3·2‐fold down‐regulation of TLR4 expression [PBS‐treated BMDC mean fluorescence intenisty (MFI): 168·7 ± 0·7; LPS‐treated BMDC MFI: 53·0 ± 1·0; P < 0·0001] in LPS‐primed BMDC and a corresponding 1·7‐fold up‐regulation of CD14 co‐receptor expression (PBS‐treated BMDC MFI: 15941·0 ± 385·6; LPS‐treated BMDC MFI: 27823 ± 475·8; P < 0·0001; Fig. 3a).…”

Section: Resultssupporting

confidence: 94%

“…Most recently RelB inhibitor‐treated autologous DC have shown efficacy in a Phase 1 clinical trial of patients with rheumatoid arthritis 13. Interestingly, although most of the studies investigating ET have been in vitro studies in which macrophages,39, 75 and less so DC,35 are refractory to a second challenge with LPS (“homotolerance”) a few studies have shown that macrophages pre‐exposed to one TLR‐agonist become unresponsive to challenge with another TLR‐agonist (“heterotolerance”). For instance, LPS‐primed macrophages fail to respond to a second challenge with extracts from other Gram‐negative bacteria 37, 64, 76.…”

Section: Discussionmentioning

confidence: 99%

“…Lipopolysaccharide‐activated macrophages and DC become refractory to further stimulation with LPS,33 a phenomenon known as endotoxin tolerance (ET), which has been attributed to various factors including: (i) the blockade of intracellular signalling events and subsequent gene re‐programming; (ii) up‐regulation of anti‐inflammatory cytokines like interleukin‐10 (IL‐10) and transforming growth factor‐ β (TGF‐ β ); and (iii) down‐regulation of surface expression of the TLR4 receptor 34. The majority of studies in myeloid cells on ET have been conducted using macrophages and have shown decreased phosphorylation levels of NF‐ κ B as well as other signalling molecules such as p38 mitogen‐activated protein kinase (p38 MAPK) and c‐Jun N‐terminal kinase (JNK) while displaying increased levels of phosphorylated extracellular signal‐regulated kinase and IL‐10 secretion 35, 36, 37, 38, 39. In further studies it was shown that previous exposure to LPS led to impaired activation of TANK‐binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) signalling through TIR‐domain‐containing adapter‐inducing interferon‐ β (TRIF) pathway,38, 40 which has been attributed to the lipid A component of LPS 41.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

et al. 2016

View full text Add to dashboard Cite

SummaryExposure of bone‐marrow‐derived dendritic cells (BMDC) to high‐dose ultrapure lipopolysaccharide for 24 hr (LPS‐primed BMDC) enhances their potency in preventing inter‐photoreceptor retinoid binding protein: complete Freund's adjuvant‐induced experimental autoimmune uveoretinitis (EAU). LPS‐primed BMDC are refractory to further exposure to LPS (= endotoxin tolerance), evidenced here by decreased phosphorylation of TANK‐binding kinase 1, interferon regulatory factor 3 (IRF3), c‐Jun N‐terminal kinase and p38 mitogen‐activated protein kinase as well as impaired nuclear translocation of nuclear factor κB (NF‐κB) and IRF3, resulting in reduced tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), IL‐12 and interferon‐β secretion. LPS‐primed BMDC also show reduced surface expression of Toll‐like receptor‐4 and up‐regulation of CD14, followed by increased apoptosis, mediated via nuclear factor of activated T cells (NFATc)‐2 signalling. LPS‐primed BMDC are not only homotolerant to LPS but are heterotolerant to alternative pathogen‐associated molecular pattern ligands, such as mycobacterial protein extract (Mycobacterium tuberculosis). Specifically, while M. tuberculosis protein extract induces secretion of IL‐1β, TNF‐α and IL‐6 in unprimed BMDC, LPS‐primed BMDC fail to secrete these cytokines in response to M. tuberculosis. We propose that LPS priming of BMDC, by exposure to high doses of LPS for 24 hr, stabilizes their tolerogenicity rather than promoting immunogenicity, and does so by multiple mechanisms, namely (i) generation of tolerogenic apoptotic BMDC through CD14:NFATc signalling; (ii) reduction of NF‐κB and IRF3 signalling and downstream pro‐inflammatory cytokine production; and (iii) blockade of inflammasome activation.

show abstract

Section: Resultssupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Compared to GM-DCs, FL-DCs expressed significantly higher levels of mRNA for the cDC-specific transcription factor Zbtb46 (25, 26) (Figure 1F). In contrast, activated GM-DCs highly expressed Nos2 , consistent with a moDC phenotype (27) (Figure 1F). Based on these observations, we concluded that FL-DCs and GM-DCs corresponded to cDCs and moDCs, respectively.…”

Section: Resultsmentioning

confidence: 92%

Epigenetic Control of Ccr7 Expression in Distinct Lineages of Lung Dendritic Cells

Moran

Nakano

Kondilis-Mangum

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Adaptive immune responses to inhaled allergens are induced following CCR7-dependent migration of pre-DC (precursor of DC)-derived conventional dendritic cells (cDCs) from the lung to regional lymph nodes (LN). However, monocyte-derived (mo) DCs in the lung express very low levels of Ccr7, and consequently do not migrate efficiently to LN. To investigate the molecular mechanisms that underlie this dichotomy, we studied epigenetic modifications at the Ccr7 locus of murine cDCs and moDCs. When expanded from bone marrow precursors, moDCs were enriched at the Ccr7 locus for trimethylation of histone 3 lysine 27 (H3K27me3), a modification associated with transcriptional repression. Similarly, moDCs prepared from the lung also displayed increased levels of H3K27me3 at the Ccr7 promoter compared with migratory cDCs from that organ. Analysis of DC progenitors revealed that epigenetic modification of Ccr7 does not occur early during DC lineage commitment because monocytes and pre-DCs both had low levels of Ccr7-associated H3K27me3. Rather, Ccr7 is gradually silenced during the differentiation of monocytes to moDCs. Thus, epigenetic modifications of the Ccr7 locus control the migration, and therefore the function of DCs in vivo. These findings suggest that manipulating epigenetic mechanisms might be a novel approach to control DC migration and thereby improve DC-based vaccines and treat inflammatory diseases of the lung.

show abstract

“…Patients with COPD also manifest increased oxidative stress in the airways [6], and exposure to either ozone or cigarette smoke extract induces p38 MAPK activation [4, 7]. Bacterial or viral infection is a common trigger for COPD exacerbations, and exposure to LPS induces p38 MAPK activation in rat peritoneal macrophages and dendritic cells as well as an increase expression of inflammatory mediators [8, 9]. Activation of p38 MAPK is also implicated in inhibition of glucocorticoid function induced by pro-inflammatory cytokines such as TNFα, IL-1α and IL-13 [10-13].…”

Section: P38 Map Kinasementioning

confidence: 99%

p38 MAPK inhibitors, IKK2 inhibitors, and TNFα inhibitors in COPD

Banerjee¹,

Koziol‐White²,

Panettieri³

2012

Current Opinion in Pharmacology

View full text Add to dashboard Cite

COPD represents a major respiratory disorder, causing significant morbidity and mortality throughout the world. While therapies exist for COPD, they are not always effective, and many patients experience exacerbations and morbidity despite current therapies. Study of the molecular mechanisms involved in the underlying physiological manifestations of COPD has yielded multiple new targets for therapeutic intervention. In this review, we discuss signaling pathways involved in COPD pathogenesis and review clinical studies of p38 MAPK inhibitors, TNFα inhibitors, and IKK2 inhibitors as potential COPD therapies.

show abstract

LPS response and endotoxin tolerance in Flt-3L-induced bone marrow-derived dendritic cells

Cited by 13 publications

References 37 publications

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

Epigenetic Control of Ccr7 Expression in Distinct Lineages of Lung Dendritic Cells

p38 MAPK inhibitors, IKK2 inhibitors, and TNFα inhibitors in COPD

Contact Info

Product

Resources

About