title: M2 macrophages exhibit higher sensitivity to oxLDL-induced lipotoxicity than other monocyte/macrophage subtypes.
abstract: BACKGROUND
  In 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.
  
  
  RESULTS
  The 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).
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Cardiff School of Health Sciences, University of Wales Institute Cardiff, UWIC Llandaf Campus, CARDIFF CF5 2YB, UK.
authors.forename: Suleiman A
authors.initials: SA
authors.lastname: Isa
authors.forename: José S
authors.initials: JS
authors.lastname: Ruffino
authors.forename: Maninder
authors.initials: M
authors.lastname: Ahluwalia
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Thomas
authors.forename: Keith
authors.initials: K
authors.lastname: Morris
authors.forename: Richard
authors.initials: R
authors.lastname: Webb
mesh_terms: D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D016764:Cell Polarity; D002470:Cell Survival; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D015870:Gene Expression; D005819:Genetic Markers; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D061251:Primary Cell Culture; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1
chemical_list: C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D005819:Genetic Markers; D006360:Heat-Shock Proteins; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D037181:Lectins, C-Type; D008077:Lipoproteins, LDL; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C099252:oxidized low density lipoprotein; D051742:Transcription Factor CHOP; D002118:Calcium