LPS- orPseudomonas aeruginosa-mediated activation of the macrophage TLR4 signaling cascade depends on membrane lipid composition

Abstract

It is well known that PUFA impede the LPS-mediated activation of the transcription factor NFkappaB. However, the underlying mode of action has not been clarified yet. To address this issue in a comprehensive approach, we used the monocyte/macrophage cell line RAW264.7 to investigate the consequences of a PUFA supplementation on the TLR4 pathway with a focus on (i) the gene expression of TLR4 itself as well as of its downstream mediators, (ii) the membrane microdomain localization of TLR4 and CD14, (iii) the stimulation-induced interaction of TLR4 and CD14. Our data indicate that the impairment of the TLR4-mediated cell activation by PUFA supplementation is not due to changes in gene expression of mediator proteins of the signaling cascade. Rather, our data provide evidence that the PUFA enrichment of macrophages affects the TLR4 pathway at the membrane level. PUFA incorporation into membrane lipids induces a reordering of membrane microdomains thereby affecting cellular signal transduction. It is important to note that this remodeling of macrophage rafts has no adverse effect on cell viability. Hence, microdomain disruption via macrophage PUFA supplementation has a potential as non-toxic strategy to attenuate inflammatory signaling.

WITHDRAWN: The extract of a Traditional Chinese Medicine alleviates Hepatic Fibrosis of Rats by inhibiting NF-κB activation and upregulating BAMBI in Hepatic Stellate Cells

“…BAMBI was a TGF-β pseudoreceptor ,and down-regulation of BAMBI made HSCs beccome more sensitive to TGF-β [18], that was the main mechanism of endotoxin-induced hepatic brosis [19,20]. HSCs was the naïve cells that responds to LPS by TLR4 [21], BAMBI was down-regulated after TLR4-MyD88-NF-κB pathway was activated in HSCs [22].…”

“…Activated HSCs expresses TLR4 and had a higher response to LPS [21]. LPS was a de nitive ligand of TLR4, it activated HSCs through the MyD88-NF-κB pathway.…”

Membrane lipids and cell signaling

“…Nonetheless, the mechanisms associated with this process have remained elusive until recently. In an elegant paper by Schoeniger and colleagues, the authors demonstrated that, unlike the predicted mechanism at the level of gene expression, PUFA enrichment affects TLR4 at the membrane [26**]. In fact, the findings provide evidence that PUFAs can disrupt PM microdomains and significantly impair stimulation of TLR4 [27].…”

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“…Возбуждение РАМР Pseudomonas aeruginosa TLR альвеолярных макрофагов приводит к секреции ими провоспалительных цитокинов (TNF α, IL 6) и некоторых хемокинов, в част ности макрофагального провоспалительного протеина 1α (CCL3/MIP 1α), активно рекрутирующего нейтрофилы [78,84] [44]. Также у людей с нейтропенией, обусло вленной химиотерапией, наблюдается высокая частота встречаемости синегнойной инфекции [50].…”