title: IL-22 is induced by S100/calgranulin and impairs cholesterol efflux in macrophages by downregulating ABCG1.
abstract: S100A8/9 and S100A12 are emerging biomarkers for disease activity of autoimmune and cardiovascular diseases. We demonstrated previously that S100A12 accelerates atherosclerosis accompanied by large cholesterol deposits in atherosclerotic lesions of apoE-null mice. The objective of this study was to ascertain whether S100/calgranulin influences cholesterol homeostasis in macrophages. Peritoneal macrophages from transgenic mice expressing human S100A8/9 and S100A12 in myeloid cells [human bacterial artificial chromosome (hBAC)/S100] have increased lipid content and reduced ABCG1 expression and [(3)H]cholesterol efflux compared with WT littermates. This was associated with a 6-fold increase in plasma interleukin (IL)-22 and increased IL-22 mRNA in splenic T cells. These findings are mediated by the receptor for advanced glycation endproducts (RAGE), because hBAC/S100 mice lacking RAGE had normal IL-22 expression and normal cholesterol efflux. In vitro, recombinant IL-22 reduced ABCG1 expression and [(3)H]cholesterol efflux in THP-1 macrophages, while recombinant S100A12 had no effect on ABCG1 expression. In conclusion, S100/calgranulin has no direct effect on cholesterol efflux in macrophages, but rather promotes the secretion of IL-22, which then directly reduces cholesterol efflux in macrophages by decreasing the expression of ABCG1.
authors.affiliation: Departments of Medicine University of Chicago, Chicago, IL.
authors.forename: Bijoy
authors.initials: B
authors.lastname: Chellan
authors.forename: Ling
authors.initials: L
authors.lastname: Yan
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sontag
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Reardon
authors.forename: Marion A
authors.initials: MA
authors.lastname: Hofmann Bowman
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000067616:S100A12 Protein; D000097043:Interleukin-22
chemical_list: D018528:ATP-Binding Cassette Transporters; D040501:Calgranulin A; D040502:Calgranulin B; D002784:Cholesterol; D007378:Interleukins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D009418:S100 Proteins; D000067616:S100A12 Protein; D000097043:Interleukin-22; C090441:S100A12 protein, human
keywords: S100A12; cholesterol transporters; interleukin-22; peritoneal macrophages; receptor for advanced glycation endproducts