title: Extracellular low pH modulates phosphatidylserine-dependent phagocytosis in macrophages by increasing stabilin-1 expression.
abstract: Microenvironmental acidosis is a common feature of inflammatory loci, in which clearance of apoptotic cells is necessary for the resolution of inflammation. Although it is known that a low pH environment affects immune function, its effect on apoptotic cell clearance by macrophages has not been fully investigated. Here, we show that treatment of macrophages with low pH medium resulted in increased expression of stabilin-1 out of several receptors, which are known to be involved in PS-dependent removal of apoptotic cells. Reporter assays showed that the -120/-1 region of the mouse stabilin-1 promoter was a low pH-responsive region and provided evidence that extracellular low pH mediated transcriptional activation of stabilin-1 via Ets-2. Furthermore, extracellular low pH activated JNK, thereby inducing translocation of Ets-2 into the nucleus. When macrophages were preincubated with low pH medium, phagocytosis of phosphatidylserine-exposed red blood cells and phosphatidylserine-coated beads by macrophages was enhanced. Blockade of stabilin-1 in macrophages abolished the enhancement of phagocytic activity by low pH. Thus, our results demonstrate that a low pH microenvironment up-regulates stabilin-1 expression in macrophages, thereby modulating the phagocytic capacity of macrophages, and suggest roles for stabilin-1 and Ets-2 in the maintenance of tissue homeostasis by the immune system.
authors.affiliation: Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, 700-422, Republic of Korea.
authors.forename: Seung-Yoon
authors.initials: SY
authors.lastname: Park
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Bae
authors.forename: Mi-Jin
authors.initials: MJ
authors.lastname: Kim
authors.forename: Mei Lan
authors.initials: ML
authors.lastname: Piao
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
mesh_terms: D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002460:Cell Line; D005110:Extracellular Space / Q000737:chemistry* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis; D010718:Phosphatidylserines / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D015533:Transcriptional Activation
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D010718:Phosphatidylserines; C486732:Stab1 protein, mouse; D048670:MAP Kinase Kinase 4