Macrophage molecular signaling and inflammatory responses during ingestion of atherogenic lipoproteins are modulated by complement protein C1q.
BACKGROUND AND AIMS
This study investigated the effect of innate immune protein C1q on macrophage programmed responses during the ingestion of atherogenic lipoproteins. C1q plays a dual role in atherosclerosis where activation of complement by C1q is known to drive inflammation and promote disease progression. However, C1q is atheroprotective in early disease using mouse models. Our previous studies have highlighted a non-complement associated role for C1q in polarizing macrophages towards an M2-like anti-inflammatory phenotype during ingestion of targets such as atherogenic lipoproteins. This study aims to investigate the molecular mechanisms involved.


METHODS
We investigated the molecular signaling mechanisms involved in macrophage polarization using an unbiased examination of gene expression profiles in human monocyte derived macrophages ingesting oxidized or acetylated low density lipoproteins in the presence or absence of C1q.


RESULTS
Expression of genes involved in Janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling, peroxisome proliferator activating receptor (PPAR) signaling and toll-like receptor (TLR) signaling were modulated by C1q in this screen. C1q was also shown to significantly suppress JAK-STAT pathway activation (a maximum 55% ± 13% reduction, p = 0.044) and increase transcriptional activation of PPARs (a maximum 229% ± 54% increase, p = 0.0002), consistent with an M2-like polarized response. These pathways were regulated in macrophages by C1q bound to different types of modified atherogenic lipoprotein and led to a reduction in the release of pro-inflammatory cytokine IL-6.


CONCLUSIONS
This study identifies potential molecular mechanisms for the beneficial role C1q plays in early atherosclerosis.
['Ho|Minh-Minh|MM|', 'Manughian-Peter|Ayla|A|', 'Spivia|Weston R|WR|', 'Taylor|Adam|A|', 'Fraser|Deborah A|DA|']
D000818:Animals D050197:Atherosclerosis D002467:Cell Nucleus D015922:Complement C1q D018450:Disease Progression D006801:Humans D007113:Immunity, Innate D007249:Inflammation D015850:Interleukin-6 D008074:Lipoproteins D008264:Macrophages D051379:Mice D010100:Oxygen D047495:PPAR gamma D047492:Peroxisome Proliferator-Activated Receptors D010641:Phenotype D000067996:RAW 264.7 Cells D050794:STAT1 Transcription Factor D015398:Signal Transduction D014158:Transcription, Genetic
Innate Atherosclerosis Inflammation JAK-STAT PPAR LDL