title: Suppression of chronic damage in renal allografts by Liver X receptor (LXR) activation relevant contribution of macrophage LXRα.
abstract: Liver X receptors (LXR)-α,β regulate intracellular cholesterol homeostasis and inhibit inflammatory gene expression. We studied the effects of the LXRα,β-agonist GW3965 on acute and chronic organ damage in the F344-LEW rat kidney transplantation model. In addition, to gain LXR isoform and cell-specific insights BALB/c kidneys were transplanted into mice with macrophage overexpression of LXRα (mLXRα-tg) and evaluated 7 and 42 days after transplantation. After 56 days GW3965 improved significantly function and morphology of rat kidney allografts by substantial reduction of mononuclear cell infiltrate and fibrosis; in vitro GW3965 reduced inflammatory activity of bone marrow-derived macrophages (BMDMs) and alloreactivity of T cells. Kidneys transplanted into mLXRα-tg mice were also protected from development of chronic allograft dysfunction. Similarly to GW3965-activated BMDMs, mLXRα-tg macrophages secreted significantly less monocyte chemoattractant protein 1 and macrophage inflammatory protein 1β. Interestingly, 7 days after transplantation, when the total number of intragraft macrophages did not differ, evidently more arginase 1- and mannose receptor C type 1-positive cells were found in LXR rat and mice kidney allografts; in vitro both LXR activation by GW3965 and mLXRα overexpression accentuated the induction of alternative activation of BMDMs by IL-4/IL-13, suggesting an additional mechanism by LXRs to prevent graft damage. The results highlight the relevance of macrophage LXRα in allograft rejection and prevention of fibrosis.
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Kiss
authors.forename: Zoran
authors.initials: Z
authors.lastname: Popovic
authors.forename: Jens
authors.initials: J
authors.lastname: Bedke
authors.forename: Shijun
authors.initials: S
authors.lastname: Wang
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Bonrouhi
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.forename: Paula
authors.initials: P
authors.lastname: Stettner
authors.forename: Daniel
authors.initials: D
authors.lastname: Teupser
authors.forename: Joachim
authors.initials: J
authors.lastname: Thiery
authors.forename: Stefan
authors.initials: S
authors.lastname: Porubsky
authors.forename: Judith
authors.initials: J
authors.lastname: Adams
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D015153:Blotting, Western; D018925:Chemokines / Q000378:metabolism; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000517:prevention & control*; D005434:Flow Cytometry; D006084:Graft Rejection / Q000378:metabolism / Q000517:prevention & control*; D007124:Immunoenzyme Techniques; D016030:Kidney Transplantation; D008024:Ligands; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous
chemical_list: D001565:Benzoates; D001596:Benzylamines; D018925:Chemokines; D016207:Cytokines; C473027:GW 3965; D008024:Ligands; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger