Similarities and differences of innate immune responses elicited by smooth and rough LPS

Zanoni, Ivan; Bodio, Caterina; Broggi, Achille; Ostuni, Renato; Caccia, Michele; Collini, Maddalena; Venkatesh, Aparna; Spreafico, Roberto; Capuano, Giusy; Granucci, Francesca

doi:10.1016/j.imlet.2011.12.002

Cited by 47 publications

(37 citation statements)

References 24 publications

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“…It should be noted, however, that NFAT must ultimately bind to additional transcription factors, such as AP1 to regulate gene expression. In DCs, LPS engagement of Toll-like receptor 4 (TLR4) and CD14 activates Src-family kinase and PLC-␥2 to drive the production of IP 3 and diacylglycerol 8,14 (Figure 1). Interestingly, smooth LPS-mediated activation of DCs is fully dependent on an extracellular source of Ca 2ϩ 8,14 ; and hence, the authors speculate that DCs, unlike lymphocytes, may not use Ca 2ϩ derived from the endoplasmic reticulum to support activation.…”

Section: Calcineurin/nfat Signalingmentioning

confidence: 99%

“…In DCs, LPS engagement of Toll-like receptor 4 (TLR4) and CD14 activates Src-family kinase and PLC-␥2 to drive the production of IP 3 and diacylglycerol 8,14 (Figure 1). Interestingly, smooth LPS-mediated activation of DCs is fully dependent on an extracellular source of Ca 2ϩ 8,14 ; and hence, the authors speculate that DCs, unlike lymphocytes, may not use Ca 2ϩ derived from the endoplasmic reticulum to support activation. 14,15 Instead, IP 3 may bind to cognate receptors on the plasma membrane to open Ca 2ϩ channels, leading to Ca 2ϩ influx and activation of calcineurin/NFAT signaling ( Figure 1).…”

Section: Calcineurin/nfat Signalingmentioning

confidence: 99%

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NFAT control of innate immunity

Frič

Zelante

Wong

et al. 2012

Blood

209

179

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Section: Calcineurin/nfat Signalingmentioning

confidence: 99%

Section: Calcineurin/nfat Signalingmentioning

confidence: 99%

NFAT control of innate immunity

Frič

Zelante

Wong

et al. 2012

Blood

209

179

View full text Add to dashboard Cite

“…We have recently shown that different LPS species may elicit slightly different innate responses by initiating different signaling pathways (17). Therefore, we evaluated whether LPS from different sources were equally able to induce mPGES-1, COX-2, and PGE 2 production.…”

Section: Introductionmentioning

confidence: 99%

CD14 and NFAT mediate lipopolysaccharide-induced skin edema formation in mice

Zanoni¹,

Ostuni²,

Barresi³

et al. 2012

J. Clin. Invest.

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Inflammation is a multistep process triggered when innate immune cells -for example, DCs -sense a pathogen or injured cell or tissue. Edema formation is one of the first steps in the inflammatory response; it is fundamental for the local accumulation of inflammatory mediators. Injection of LPS into the skin provides a model for studying the mechanisms of inflammation and edema formation. While it is known that innate immune recognition of LPS leads to activation of numerous transcriptional activators, including nuclear factor of activated T cells (NFAT) isoforms, the molecular pathways that lead to edema formation have not been determined. As PGE 2 regulates many proinflammatory processes, including swelling and pain, and it is induced by LPS, we hypothesized that PGE 2 mediates the local generation of edema following LPS exposure. Here, we show that tissue-resident DCs are the main source of PGE 2 and the main controllers of tissue edema formation in a mouse model of LPS-induced inflammation. LPS exposure induced expression of microsomal PGE synthase-1 (mPGES-1), a key enzyme in PGE 2 biosynthesis. mPGES-1 activation, PGE 2 production, and edema formation required CD14 (a component of the LPS receptor) and NFAT. Therefore, tissue edema formation induced by LPS is DC and CD14/NFAT dependent. Moreover, DCs can regulate free antigen arrival at the draining lymph nodes by controlling edema formation and interstitial fluid pressure in the presence of LPS. We therefore suggest that the CD14/NFAT/mPGES-1 pathway represents a possible target for antiinflammatory therapies.

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“…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. LPS priming of DC has shown similar results for activation of myeloid differentiating factor 88 (MyD88) downstream signalling35 but a decrease in activation of the TRIF pathway in endotoxin‐tolerant DC (ET‐DC) has not been reported to date.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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Similarities and differences of innate immune responses elicited by smooth and rough LPS

Cited by 47 publications

References 24 publications

NFAT control of innate immunity

NFAT control of innate immunity

CD14 and NFAT mediate lipopolysaccharide-induced skin edema formation in mice

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

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