Influence of chylomicron remnants on human monocyte activation in vitro

Background and aims Atherosclerosis is known to be an inflammatory disease and there is increasing evidence that chylomicron remnants (CMR), the lipoproteins which carry dietary fats in the blood, cause macrophage foam cell formation and inflammation. In early atherosclerosis the frequency of activated monocytes in the peripheral circulation is increased, and clearance of CMR from blood may be delayed, however, whether CMR contribute directly to monocyte activation and subsequent egress into the arterial wall has not been established. Here, the contribution of CMR to activation of monocyte pro-inflammatory pathways was assessed using an in vitro model. Methods and results Primary human monocytes and CMR-like particles (CRLP) were used to measure several endpoints of monocyte activation. Treatment with CRLP caused rapid and prolonged generation of reactive oxygen species by monocytes. The pro-inflammatory chemokines MCP-1 and IL-8 were secreted in nanogram quantities by the cells in the absence of CRLP. IL-8 secretion was transiently increased after CRLP treatment, and CRLP maintained secretion in the presence of pharmacological inhibitors of IL-8 production. In contrast, exposure to CRLP significantly reduced MCP-1 secretion. Chemotaxis towards MCP-1 was increased in monocytes pre-exposed to CRLP and was reversed by addition of exogenous MCP-1. Conclusion Our findings indicate that CRLP activate human monocytes and augment their migration in vitro by reducing cellular MCP-1 expression. Our data support the current hypothesis that CMR contribute to the inflammatory milieu of the arterial wall in early atherosclerosis, and suggest that this may reflect direct interaction with circulating blood monocytes.

Suppression of nuclear factor-κB activity in macrophages by chylomicron remnants: modulation by the fatty acid composition of the particles

Current evidence indicates that chylomicron remnants (CMR) induce macrophage foam cell formation, an early event in atherosclerosis. Inflammation also plays a part in atherogenesis and the transcription factor nuclear factor-kappaB (NF-kappaB) has been implicated. In this study, the influence of CMR on the activity of NF-kappaB in macrophages and its modulation by the fatty acid composition of the particles were investigated using macrophages derived from the human monocyte cell line THP-1 and CMR-like particles (CRLPs). Incubation of THP-1 macrophages with CRLPs caused decreased NF-kappaB activation and downregulated the expression of phospho-p65-NF-kappaB and phospho-IkappaBalpha (pIkappaBalpha). Secretion of the inflammatory cytokines tumour necrosis factor alpha, interleukin-6 and monocyte chemoattractant protein-1, which are under NF-kappaB transcriptional control, was inhibited and mRNA expression for cyclooxygenase-2, an NF-kappaB target gene, was reduced. CRLPs enriched in polyunsaturated fatty acids compared with saturated or monounsaturated fatty acids had a markedly greater inhibitory effect on NF-kappaB binding to DNA and the expression of phospho-p65-NF-kappaB and pIkappaB. Lipid loading of macrophages with CRLPs enriched in polyunsaturated fatty acids compared with monounsaturated fatty acids or saturated fatty acids also increased the subsequent rate of cholesterol efflux, an effect which may be linked to the inhibition of NF-kappaB activity. These findings demonstrate that CMR suppress NF-kappaB activity in macrophages, and that this effect is modulated by their fatty acid composition. This downregulation of inflammatory processes in macrophages may represent a protective effect of CMR which is enhanced by dietary polyunsaturated fatty acids.

The induction of macrophages foam cell formation by chylomicron remnants

The accumulation of foam cells in the artery wall causes fatty streaks, the first lesions in atherosclerosis. LDL (low-density lipoprotein) plays a major role in foam cell formation, although prior oxidation of the particles is required. Recent studies, however, have provided considerable evidence to indicate that CMRs (chylomicron remnants), which carry dietary lipids in the blood, induce foam cell formation without oxidation. We have shown that CMRs are taken up by macrophages and induce accumulation of both triacylglycerol and cholesterol, and that the rate of uptake and amount of lipid accumulated is influenced by the type of dietary fat in the particles. Furthermore, oxidation of CMRs, in striking contrast with LDL, inhibits, rather than enhances, their uptake and induction of lipid accumulation. In addition, the lipid accumulated after exposure of macrophages to CMRs is resistant to efflux, and this may be due to its sequestration in lysosomes. These findings demonstrate that CMRs induce pro-atherogenic changes in macrophages, and that their effects may be modulated by dietary factors including oxidized fats, lipophilic antioxidants and the type of fat present.

Fatty acids composition of Chylomicron remnants like particles influences their uptake and induction of lipid accumulation in macrophages.

The influence of the fatty acid composition of chylomicron remnant-like particles (CRLPs) on their uptake and induction of lipid accumulation in macrophages was studied. CRLPs containing triacylglycerol enriched in saturated, monounsaturated, n−6 or n−3 polyunsaturated fatty acids derived from palm, olive, corn or fish oil, respectively, and macrophages derived from the human monocyte cell line THP-1 were used. Lipid accumulation (triacylglycerol and cholesterol) in the cells was measured after incubation with CRLPs for 5, 24 and 48 h, and uptake over 24 h was determined using CRLPs radiolabelled with [3H]triolein. Total lipid accumulation in the macrophages was significantly greater with palm CRLPs than with the other three types of particle. This was mainly due to increased triacylglycerol concentrations, whereas changes in cholesterol concentrations did not reach significance. There were no significant differences in lipid accumulation after incubation with olive, corn or fish CRLPs. Palm and olive CRLPs were taken up by the cells at a similar rate, which was considerably faster than that observed with corn and fish CRLPs. These findings demonstrate that CRLPs enriched in saturated or monounsaturated fatty acids are taken up more rapidly by macrophages than those enriched in n−6 or n−3 polunsaturated fatty acids, and that the faster uptake rate results in greater lipid accumulation in the case of saturated fatty acid-rich particles, but not monounsaturated fatty acid-rich particles. Thus, dietary saturated fatty acids carried in chylomicron remnants may enhance their propensity to induce macrophage foam cell formation.

The Visual Representation of a Systematic Metaphor in a UK Media Text

Much has been written on the organizational power of metaphor in discourse, eg on metaphor ‘chains’ and ‘clusters’ of linguistic metaphor in discourse (Koller 2003, Cameron & Stelma 2004, Semino 2008) and the role of extended and systematic metaphor in organizing long stretches of language, even whole texts (Cameron et al 2009, Cameron & Maslen 2010, Deignan et al 2013, Semino et al 2013). However, at times, this work belies the intricacies of how a single metaphoric idea can impact on a text. The focus of this paper is a UK media article derived from a HM Treasury press release on alleviating poverty. The language of the article draws heavily on orientational (spatial) metaphors, particularly metaphors of movement around GOOD IS UP. Although GOOD IS UP can be considered a single metaphoric idea, the picture the reader builds up as they move line by line through this text is complex and multifaceted. I take the idea of “building up a picture” literally in order to investigate the schema of motion relating to GOOD IS UP. To do this, fifteen informants (Masters students at a London university), tutored in Cognitive Metaphor Theory, were asked to read the article and underline words and expressions they felt related to GOOD IS UP. The text was then read back to the informant with emphasis given to the words they had underlined, while they drew a pictorial representation of the article based on the meanings of these words, integrating their drawings into a single picture as they went along. I present examples of the drawings the informants produced. I propose that using Metaphor-led Discourse Analysis to produce visual material in this way offers useful insights into how metaphor contributes to meaning making at text level. It shows how a metaphoric idea, such as GOOD IS UP, provides the text producer with a rich and versatile meaning-making resource for constructing text; and gives a ‘mind-map’ of how certain aspects of a media text are decoded by the text receiver. It also offers a partial representation of the elusive, intermediate ‘deverbalized’ stage of translation (Lederer 1987), where the sense of the source text is held in the mind before it is transferred to the target language. References Cameron, L., R. Maslen, Z. Todd, J. Maule, P. Stratton & N. Stanley. 2009. ‘The discourse dynamic approach to metaphor and metaphor-led analysis’. Metaphor and Symbol, 24(2), 63-89. Cameron, L. & R. Maslen (eds). 2010. Metaphor Analysis: Research Practice in Applied Linguistics, Social Sciences and Humanities. London: Equinox. Cameron, L. & J. Stelma. 2004. ‘Metaphor Clusters in Discourse’. Journal of Applied Linguistics, 1(2), 107-136. Deignan, A., J. Littlemore & E. Semino. 2013. Figurative Language, Genre and Register. Cambridge: Cambridge University Press. Koller, V. 2003. ‘Metaphor Clusters, Metaphor Chains: Analyzing the Multifunctionality of Metaphor in Text’. metaphorik.de, 5, 115-134. Lederer, M. 1987. ‘La théorie interprétative de la traduction’ in Retour à La Traduction. Le Francais dans Le Monde. Semino, E. 2008. Metaphor in Discourse. Cambridge: Cambridge University Press. Semino, E., A. Deignan & J. Littlemore. 2013. ‘Metaphor, Genre, and Recontextualization’. Metaphor and Symbol. 28(1), 41-59.