title: SR-A ligand and M-CSF dynamically regulate SR-A expression and function in primary macrophages via p38 MAPK activation.
abstract: BACKGROUND
  Inflammation is characterized by dynamic changes in the expression of cytokines, such as M-CSF, and modifications of lipids and proteins that result in the formation of ligands for Class A Scavenger Receptors (SR-A). These changes are associated with altered SR-A expression in macrophages; however, the intracellular signal pathways involved and the extent to which SR-A ligands regulate SR-A expression are not well defined. To address these questions, SR-A expression and function were examined in resident mouse peritoneal macrophages incubated with M-CSF or the selective SR-A ligand acetylated-LDL (AcLDL).
  
  
  RESULTS
  M-CSF increased SR-A expression and function, and required the specific activation of p38 MAPK, but not ERK1/2 or JNK. Increased SR-A expression and function returned to basal levels 72 hours after removing M-CSF. We next determined whether prolonged incubation of macrophages with SR-A ligand alters SR-A expression. In contrast to most receptors, which are down-regulated by chronic exposure to ligand, SR-A expression was reversibly increased by incubating macrophages with AcLDL. AcLDL activated p38 in wild-type macrophages but not in SR-A-/- macrophages, and p38 activation was specifically required for AcLDL-induced SR-A expression.
  
  
  CONCLUSIONS
  These results demonstrate that in resident macrophages SR-A expression and function can be dynamically regulated by changes in the macrophage microenvironment that are typical of inflammatory processes. In particular, our results indicate a previously unrecognized role for ligand binding to SR-A in up-regulating SR-A expression and activating p38 MAPK. In this way, SR-A may modulate inflammatory responses by enhancing macrophage uptake of modified protein/lipid, bacteria, and cell debris; and by regulating the production of inflammatory cytokines, growth factors, and proteolytic enzymes.
authors: Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors: Dejan
authors: D
authors: Nikolic
authors: Lindsay
authors: L
authors: Calderon
authors: Liqin
authors: L
authors: Du
authors: Steven R
authors: SR
authors: Post
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D007155:Immunologic Factors / Q000378:metabolism / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D007155:Immunologic Factors; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D051117:Scavenger Receptors, Class A; C032629:acetyl-LDL; D016173:Macrophage Colony-Stimulating Factor; D048051:p38 Mitogen-Activated Protein Kinases