title: Macrophage molecular signaling and inflammatory responses during ingestion of atherogenic lipoproteins are modulated by complement protein C1q.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  This study identifies potential molecular mechanisms for the beneficial role C1q plays in early atherosclerosis.
authors: Department of Biological Sciences, California State University Long Beach, Long Beach, CA, USA.
authors: Minh-Minh
authors: MM
authors: Ho
authors: Department of Biological Sciences, California State University Long Beach, Long Beach, CA, USA.
authors: Ayla
authors: A
authors: Manughian-Peter
authors: Department of Biological Sciences, California State University Long Beach, Long Beach, CA, USA.
authors: Weston R
authors: WR
authors: Spivia
authors: Department of Biological Sciences, California State University Long Beach, Long Beach, CA, USA.
authors: Adam
authors: A
authors: Taylor
authors: Department of Biological Sciences, California State University Long Beach, Long Beach, CA, USA. Electronic address: Deborah.fraser@csulb.edu.
authors: Deborah A
authors: DA
authors: Fraser
mesh_terms: D000818:Animals; D050197:Atherosclerosis; D002467:Cell Nucleus / Q000378:metabolism; D015922:Complement C1q / Q000378:metabolism*; D018450:Disease Progression; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D010100:Oxygen / Q000737:chemistry; D047495:PPAR gamma / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D010641:Phenotype; D000067996:RAW 264.7 Cells; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D015850:Interleukin-6; D008074:Lipoproteins; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015922:Complement C1q; D010100:Oxygen
keywords: Atherosclerosis; Inflammation; Innate; JAK-STAT; LDL; PPAR