<p><b>Effects of CD36 or SR-A deficiency and of anti-CD14 mAb on TNF-α and RANTES production, stimulated by 1-h incubation on ice with 1</b> μ<b>g/ml S-LPS (A-B) or R-LPS (C-D).</b> (A) Anti-CD14 mAb blocks both TNF-α and RANTES production, stimulated by S-LPS. (B) S-LPS stimulates significantly higher cytokine production in CD36-/- than in WT or SR-A-/- PEMs. (C) R-LPS-stimulated cytokine production is more strongly inhibited by anti-CD14 mAb in CD36-/- than in WT or SR-A-/- PEMs. (D) R-LPS stimulates similar cytokine production in WT, CD36-/- and SR-A-/- PEMs. Graphs show means +SEM from 4–6 independent experiments, each performed in 4 replicates. Data on graphs A and C were analyzed with one-sample t-test, and on graphs B and D with ANOVA, followed by the Dunnett’s test. *, p < 0.05.</p

Angelika Peruń (2609788)

Rafał Biedroń (718471)

Szczepan Józefowski (718473)

PLoS ONE

PubMed

Vrdlovcová, Anna

National Repository of Grey Literature

Effects of ECJ judgments on the principle of res judicata of national bodies of members states

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CD36 Differently Regulates Macrophage Responses to Smooth and Rough Lipopolysaccharide - Fig 4

Lipopolysaccharide (LPS) is the major pathogen-associated molecular pattern of Gram-negative bacterial infections, and includes smooth (S-LPS) and rough (R-LPS) chemotypes. Upon activation by LPS through CD14, TLR4/MD-2 heterodimers sequentially induce two waves of intracellular signaling for macrophage activation: the MyD88-dependent pathway from the plasma membrane and, following internalization, the TRIF-dependent pathway from endosomes. We sought to better define the role of scavenger receptors CD36 and CD204/SR-A as accessory LPS receptors that can contribute to pro-inflammatory and microbicidal activation of macrophages. We have found that CD36 differently regulates activation of mouse macrophages by S-LPS versus R-LPS. The ability of CD36 to substitute for CD14 in loading R-LPS, but not S-LPS onto TLR4/MD-2 allows CD14-independent macrophage responses to R-LPS. Conversely, S-LPS, but not R-LPS effectively stimulates CD14 binding to CD36, which favors S-LPS transfer from CD14 onto TLR4/MD-2 under conditions of low CD14 occupancy with S-LPS in serum-free medium. In contrast, in the presence of serum, CD36 reduces S-LPS binding to TLR4/MD-2 and the subsequent MyD88-dependent signaling, by mediating internalization of S-LPS/CD14 complexes. Additionally, CD36 positively regulates activation of TRIF-dependent signaling by both S-LPS and R-LPS, by promoting TLR4/MD-2 endocytosis. In contrast, we have found that SR-A does not function as a S-LPS receptor. Thus, by co-operating with CD14 in both R- and S-LPS loading onto TLR4/MD-2, CD36 can enhance the sensitivity of tissue-resident macrophages in detecting infections by Gram-negative bacteria. However, in later phases, following influx of serum to the infection site, the CD36-mediated negative regulation of MyD88-dependent branch of S-LPS-induced TLR4 signaling might constitute a mechanism to prevent an excessive inflammatory response, while preserving the adjuvant effect of S-LPS for adaptive immunity

Rafał Biedroń

Angelika Peruń

Szczepan Józefowski

Directory of Open Access Journals

CD36 Differently Regulates Macrophage Responses to Smooth and Rough Lipopolysaccharide.

Biedroń, Rafał

Peruń, Angelika

Józefowski, Szczepan

Jagiellonian Univeristy Repository

English

CD36 differently regulates macrophage responses to smooth and rough lipopolysaccharide

<div><p>Lipopolysaccharide (LPS) is the major pathogen-associated molecular pattern of Gram-negative bacterial infections, and includes smooth (S-LPS) and rough (R-LPS) chemotypes. Upon activation by LPS through CD14, TLR4/MD-2 heterodimers sequentially induce two waves of intracellular signaling for macrophage activation: the MyD88-dependent pathway from the plasma membrane and, following internalization, the TRIF-dependent pathway from endosomes. We sought to better define the role of scavenger receptors CD36 and CD204/SR-A as accessory LPS receptors that can contribute to pro-inflammatory and microbicidal activation of macrophages. We have found that CD36 differently regulates activation of mouse macrophages by S-LPS <i>versus</i> R-LPS. The ability of CD36 to substitute for CD14 in loading R-LPS, but not S-LPS onto TLR4/MD-2 allows CD14-independent macrophage responses to R-LPS. Conversely, S-LPS, but not R-LPS effectively stimulates CD14 binding to CD36, which favors S-LPS transfer from CD14 onto TLR4/MD-2 under conditions of low CD14 occupancy with S-LPS in serum-free medium. In contrast, in the presence of serum, CD36 reduces S-LPS binding to TLR4/MD-2 and the subsequent MyD88-dependent signaling, by mediating internalization of S-LPS/CD14 complexes. Additionally, CD36 positively regulates activation of TRIF-dependent signaling by both S-LPS and R-LPS, by promoting TLR4/MD-2 endocytosis. In contrast, we have found that SR-A does not function as a S-LPS receptor. Thus, by co-operating with CD14 in both R- and S-LPS loading onto TLR4/MD-2, CD36 can enhance the sensitivity of tissue-resident macrophages in detecting infections by Gram-negative bacteria. However, in later phases, following influx of serum to the infection site, the CD36-mediated negative regulation of MyD88-dependent branch of S-LPS-induced TLR4 signaling might constitute a mechanism to prevent an excessive inflammatory response, while preserving the adjuvant effect of S-LPS for adaptive immunity.</p></div

CD36 Differently Regulates Macrophage Responses to Smooth and Rough Lipopolysaccharide

http://dx.doi.org/10.1371/journal.pone.0153558

Effects of ECJ judgments on the principle of res judicata of national bodies of members states

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