Human SR-BII mediates SAA uptake and contributes to SAA pro-inflammatory signaling in vitro and in vivo

PLoS One. 2017 Apr 19;12(4):e0175824. doi: 10.1371/journal.pone.0175824. eCollection 2017.

Abstract

Serum amyloid A (SAA) is an acute phase protein with cytokine-like and chemotactic properties, that is markedly up-regulated during various inflammatory conditions. Several receptors, including FPRL-1, TLR2, TLR4, RAGE, class B scavenger receptors, SR-BI and CD36, have been identified as SAA receptors. This study provides new evidence that SR-BII, splice variant of SR-BI, could function as an SAA receptor mediating its uptake and pro-inflammatory signaling. The uptake of Alexa Fluor488 SAA was markedly (~3 fold) increased in hSR-BII-expressing HeLa cells when compared with mock-transfected cells. The levels of SAA-induced interleukin-8 secretion by hSR-BII-expressing HEK293 cells were also significantly (~3-3.5 fold) higher than those detected in control cells. Moderately enhanced levels of phosphorylation of all three mitogen-activated protein kinases, ERK1/2, and p38 and JNK, were observed in hSR-BII-expressing cells following SAA stimulation when compared with control wild type cells. Transgenic mice with pLiv-11-directed liver/kidney overexpression of hSR-BI or hSR-BII were used to assess the in vivo role of each receptor in SAA-induced pro-inflammatory response in these organs. Six hours after intraperitoneal SAA injection both groups of transgenic mice demonstrated markedly higher (~2-5-fold) expression levels of inflammatory mediators in the liver and kidney compared to wild type mice. Histological examinations of hepatic and renal tissue from SAA-treated mice revealed moderate level of damage in the liver of both transgenic but not in the wild type mice. Activities of plasma transaminases, biomarkers of liver injury, were also moderately higher in hSR-B transgenic mice when compared to wild type mice. Our findings identify hSR-BII as a functional SAA receptor that mediates SAA uptake and contributes to its pro-inflammatory signaling via the MAPKs-mediated signaling pathways.

MeSH terms

  • Animals
  • Biological Transport
  • Fluorescent Dyes / metabolism
  • Fluorobenzenes / metabolism
  • Gene Expression Regulation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Kidney / drug effects
  • Kidney / metabolism*
  • Kidney / pathology
  • Liver / drug effects
  • Liver / metabolism*
  • Liver / pathology
  • Lysosomal Membrane Proteins / genetics
  • Lysosomal Membrane Proteins / metabolism*
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Receptors, Scavenger / genetics
  • Receptors, Scavenger / metabolism*
  • Serum Amyloid A Protein / genetics
  • Serum Amyloid A Protein / metabolism*
  • Serum Amyloid A Protein / pharmacology
  • Signal Transduction
  • Transfection
  • Transgenes
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Fluorescent Dyes
  • Fluorobenzenes
  • Lysosomal Membrane Proteins
  • Receptors, Scavenger
  • SCARB2 protein, human
  • Serum Amyloid A Protein
  • Mapk1 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4

Grants and funding

This research was supported by the NIH Intramural Research Programs at the Clinical Center, NIDDK, and NHLBI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.