TitleInflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression.
Publication TypeJournal Article
Year of Publication2017
AuthorsRahman, K, Vengrenyuk, Y, Ramsey, SA, Vila, NRotllan, Girgis, NM, Liu, J, Gusarova, V, Gromada, J, Weinstock, A, Moore, KJ, Loke, P'ng, Fisher, EA
JournalJ Clin Invest
Date Published2017 Aug 01
KeywordsAnimals, Aorta, Atherosclerosis, Cell Lineage, CX3C Chemokine Receptor 1, Female, Hyperlipidemias, Inflammation, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Monocytes, Phenotype, Plaque, Atherosclerotic, Receptors, CCR2, Receptors, CCR5, Receptors, Chemokine, Sequence Analysis, RNA, STAT6 Transcription Factor, Treatment Outcome

Atherosclerosis is a chronic inflammatory disease, and developing therapies to promote its regression is an important clinical goal. We previously established that atherosclerosis regression is characterized by an overall decrease in plaque macrophages and enrichment in markers of alternatively activated M2 macrophages. We have now investigated the origin and functional requirement for M2 macrophages in regression in normolipidemic mice that received transplants of atherosclerotic aortic segments. We compared plaque regression in WT normolipidemic recipients and those deficient in chemokine receptors necessary to recruit inflammatory Ly6Chi (Ccr2-/- or Cx3cr1-/-) or patrolling Ly6Clo (Ccr5-/-) monocytes. Atherosclerotic plaques transplanted into WT or Ccr5-/- recipients showed reduced macrophage content and increased M2 markers consistent with plaque regression, whereas plaques transplanted into Ccr2-/- or Cx3cr1-/- recipients lacked this regression signature. The requirement of recipient Ly6Chi monocyte recruitment was confirmed in cell trafficking studies. Fate-mapping and single-cell RNA sequencing studies also showed that M2-like macrophages were derived from newly recruited monocytes. Furthermore, we used recipient mice deficient in STAT6 to demonstrate a requirement for this critical component of M2 polarization in atherosclerosis regression. Collectively, these results suggest that continued recruitment of Ly6Chi inflammatory monocytes and their STAT6-dependent polarization to the M2 state are required for resolution of atherosclerotic inflammation and plaque regression.

Alternate JournalJ Clin Invest
PubMed ID28650342
PubMed Central IDPMC5531402
Grant ListR01 AI093811 / AI / NIAID NIH HHS / United States
F32 AI102502 / AI / NIAID NIH HHS / United States
F30 HL131183 / HL / NHLBI NIH HHS / United States
T32 HL098129 / HL / NHLBI NIH HHS / United States
T32 GM007308 / GM / NIGMS NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
R21 AI094166 / AI / NIAID NIH HHS / United States
T32 AI007180 / AI / NIAID NIH HHS / United States
T32 AI100853 / AI / NIAID NIH HHS / United States
R01 HL084312 / HL / NHLBI NIH HHS / United States