Induction of CD36 and thrombospondin-1 in macrophages by hypoxia-inducible factor 1 and its relevance in the inflammatory process

PLoS One. 2012;7(10):e48535. doi: 10.1371/journal.pone.0048535. Epub 2012 Oct 31.

Abstract

Inflammation is part of a complex biological response of vascular tissue to pathogens or damaged cells. First inflammatory cells attempt to remove the injurious stimuli and this is followed by a healing process mediated principally by phagocytosis of senescent cells. Hypoxia and p38-MAPK are associated with inflammation, and hypoxia inducible factor 1 (HIF-1) has been detected in inflamed tissues. We aimed to analyse the role of p38-MAPK and HIF-1 in the transcriptional regulation of CD36, a class B scavenger receptor, and its ligand thrombospondin (TSP-1) in macrophages and to evaluate the involvement of this pathway in phagocytosis of apoptotic neutrophils. We have also assessed HIF-1α, p38-MAPK and CD36 immunostaining in the mucosa of patients with inflammatory bowel disease. Results show that hypoxia increases neutrophil phagocytosis by macrophages and induces the expression of CD36 and TSP-1. Addition of a p38-MAPK inhibitor significantly reduced the increase in CD36 and TSP-1 expression provoked by hypoxia and decreased HIF-1α stabilization in macrophages. Transient transfection of macrophages with a miHIF-1α-targeting vector blocked the increase in mRNA expression of CD36 and TSP-1 during hypoxia and reduced phagocytosis, thus highlighting a role for the transcriptional activity of HIF-1. CD36 and TSP-1 were necessary for the phagocytosis of neutrophils induced by hypoxic macrophages, since functional blockade of these proteins undermined this process. Immunohistochemical studies revealed CD36, HIF-1α and p38-MAPK expression in the mucosa of patients with inflammatory bowel disease. A positive and significant correlation between HIF-1α and CD36 expression and CD36 and p38-MAPK expression was observed in cells of the lamina propria of the damaged mucosa. Our results demonstrate a HIF-1-dependent up-regulation of CD36 and TSP-1 that mediates the increased phagocytosis of neutrophils by macrophages during hypoxia. Moreover, they suggest that CD36 expression in the damaged mucosa of patients with inflammatory bowel disease depends on p38-MAPK and HIF-1 activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Apoptosis / immunology
  • CD36 Antigens / metabolism*
  • Cell Line
  • Colitis, Ulcerative / genetics
  • Colitis, Ulcerative / immunology
  • Colitis, Ulcerative / metabolism
  • Crohn Disease / genetics
  • Crohn Disease / immunology
  • Crohn Disease / metabolism
  • Female
  • Humans
  • Hypoxia / immunology
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1 / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Male
  • Middle Aged
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Phagocytosis / immunology
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Stability
  • Signal Transduction
  • Thrombospondin 1 / genetics
  • Thrombospondin 1 / metabolism*
  • Young Adult
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • CD36 Antigens
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Thrombospondin 1
  • p38 Mitogen-Activated Protein Kinases

Grant support

This project was funded by SAF2010-20231 (Ministerio de Educación y Cultura), CIBERehd CD06/04/0071 (Ministerio de Sanidad y Consumo), and PROMETEO/2010/060 (Consellería de Educación, Generalitat Valenciana), Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.