M2 macrophages exhibit higher sensitivity to oxLDL-induced lipotoxicity than other monocyte/macrophage subtypes

Abstract

BackgroundIn obesity, phenotypic switches occur in macrophage populations such that the predominantly M2-polarised anti-inflammatory state seen in lean individuals changes to a predominantly M1-polarised pro-inflammatory state in those who are obese. However, the mechanisms by which these phenotypic shifts occur have not yet been fully elucidated.ResultsThe effects of oxLDL (1-40 μg/ml; 24 h) on several parameters relevant to the Unfolded Protein Response (UPR)-mediated lipotoxic effects of oxLDL (disruption of ER Ca2+ handling; activation of the UPR transcription factor XBP-1; upregulation of the UPR target genes BiP and CHOP; apoptosis; cell viability) were investigated in human primary monocyte-derived macrophages, and also in monocyte-macrophages derived from the THP-1 monocytic cell line. A consistent pattern was observed: M2-polarised macrophages were more sensitive to the lipotoxic effects of oxLDL than either non-polarised macrophages or non-differentiated monocytic cells. Specifically, M2-polarised macrophages were the only cell type to undergo significantly increased apoptosis (Primary cells: 1.23 ± 0.01 basal; THP-1-derived: 1.97 ± 0.12 basal; P < 0.05 in both cases) and decreased cell viability (Primary cells: 0.79 ± 0.04 basal; THP-1-derived: 0.67 ± 0.02 basal; P < 0.05 in both cases) when exposed to oxLDL levels similar to those seen in overweight individuals (ie. 1 μg/ml).ConclusionsWe propose that the enhanced susceptibility of M2-polarised macrophages to lipotoxicity seen in the present in vitro study could, over time, contribute to the phenotypic shift seen in obese individuals in vivo. This is because a higher degree of oxLDL-induced lipotoxic cell death within M2 macrophages could contribute to a decrease in numbers of M2 cells, and thus a relative increase in proportion of non-M2 cells, within macrophage populations. Given the pro-inflammatory characteristics of a predominantly M1-polarised state, the data presented here may constitute a useful contribution to our understanding of the origin of the pro-inflammatory nature of obesity, and of the pathogenesis of obesity-associated inflammatory disorders such as Type 2 Diabetes and atherosclerosis.

Myeloperoxidase-Oxidized LDLs Enhance an Anti-Inflammatory M2 and Antioxidant Phenotype in Murine Macrophages

“…They determined that M2 macrophages are more sensitive to the lipotoxicity induced by Ox-LDLs, as compared to M0 macrophages and to monocytes. Anew, in the latter study, only copper-oxidized LDLs were evaluated and only M0 and M2 macrophages were taken into account [ 59 ]. van Tits et al (2011) have shown that Ox-LDLs enhance proinflammatory responses stimulated by LPS in human M2 macrophages, which is in agreement with our data showing proinflammatory effects of Ox-LDLs.…”

Macrophage phenotypic subtypes diametrically regulate epithelial-mesenchymal plasticity in breast cancer cells

“…Peripheral blood mononuclear cells (PBMCs) were obtained using a previously described method [ 22 , 23 ]. Briefly, we mixed the human peripheral blood sample with an equal volume of room temperature PBS, pelleted the leukocyte/RBC fraction by centrifuging the cells 15 min at 200 × g , at room temperature.…”

Endoplasmic Reticulum Stress Pathway, the Unfolded Protein Response, Modulates Immune Function in the Tumor Microenvironment to Impact Tumor Progression and Therapeutic Response

“…Loss of UPR function in macrophages is strongly correlated with disease, including fibrosis [110], obesity-induced inflammatory disease [111,112], tuberculosis [113], and fatty liver disease [114]. These studies associate macrophage-induced inflammation via UPR signaling in these diseases, such that inhibition of UPR signaling abrogated or ablated disease.…”