title: The lymphotoxin β receptor is a potential therapeutic target in renal inflammation.
abstract: Accumulation of inflammatory cells in different renal compartments is a hallmark of progressive kidney diseases including glomerulonephritis (GN). Lymphotoxin β receptor (LTβR) signaling is crucial for the formation of lymphoid tissue, and inhibition of LTβR signaling has ameliorated several non-renal inflammatory models. Therefore, we tested whether LTβR signaling could also have a role in renal injury. Renal biopsies from patients with GN were found to express both LTα and LTβ ligands, as well as LTβR. The LTβR protein and mRNA were localized to tubular epithelial cells, parietal epithelial cells, crescents, and cells of the glomerular tuft, whereas LTβ was found on lymphocytes and tubular epithelial cells. Human tubular epithelial cells, mesangial cells, and mouse parietal epithelial cells expressed both LTα and LTβ mRNA upon stimulation with TNF in vitro. Several chemokine mRNAs and proteins were expressed in response to LTβR signaling. Importantly, in a murine lupus model, LTβR blockade improved renal function without the reduction of serum autoantibody titers or glomerular immune complex deposition. Thus, a preclinical mouse model and human studies strongly suggest that LTβR signaling is involved in renal injury and may be a suitable therapeutic target in renal diseases.
authors.affiliation: Division of Visceral & Transplantation Surgery, Swiss Hepato-Pancreato-Biliary Center, Zurich, Switzerland; Division of Nephrology, University Hospital, Zurich, Switzerland.
authors.forename: Gitta
authors.initials: G
authors.lastname: Seleznik
authors.affiliation: Division of Nephrology, University Hospital, Zurich, Switzerland; Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Harald
authors.initials: H
authors.lastname: Seeger
authors.affiliation: Institute of Virology, Technische Universität München, Helmholz Zentrum, Munich, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Bauer
authors.affiliation: Department of Immunobiology, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.affiliation: Department of Immunobiology, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Czerkowicz
authors.affiliation: Department of Immunobiology, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Papandile
authors.affiliation: Department of Immunobiology, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Uriana
authors.initials: U
authors.lastname: Poreci
authors.affiliation: Department of Immunobiology, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Dania
authors.initials: D
authors.lastname: Rabah
authors.affiliation: Department of Immunobiology, Biogen, Cambridge, Massachusetts, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Ranger
authors.affiliation: Division of Nephrology, University Hospital, Zurich, Switzerland; Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.affiliation: Division of Nephrology, University Hospital, Zurich, Switzerland; Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Maja
authors.initials: M
authors.lastname: Lindenmeyer
authors.affiliation: Division of Nephrology, University Hospital, Zurich, Switzerland; Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Division of Nephrology, University Hospital, Zurich, Switzerland; Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Ilka
authors.initials: I
authors.lastname: Edenhofer
authors.affiliation: Division of Nephrology, Medizinische Klinik und Poliklinik IV, Campus Innenstadt, University of Munich-LMU, Munich, Germany.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Anders
authors.affiliation: Division of Nephrology, Medizinische Klinik und Poliklinik IV, Campus Innenstadt, University of Munich-LMU, Munich, Germany.
authors.forename: Maciej
authors.initials: M
authors.lastname: Lech
authors.affiliation: Division of Nephrology, University Hospital, Zurich, Switzerland; Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Rudolf P
authors.initials: RP
authors.lastname: Wüthrich
authors.affiliation: Epidemiology of Microbial Diseases, School of Public Health, Yale University, New Haven, Connecticut, USA.
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Ruddle
authors.affiliation: Department of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule (RWTH) University Hospital Aachen, Aachen, Germany.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Moeller
authors.affiliation: Clinical Institute of Pathology, University of Vienna, Vienna, Austria.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Kozakowski
authors.affiliation: Clinical Institute of Pathology, University of Vienna, Vienna, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Regele
authors.affiliation: Department of Immunobiology, Biogen, Cambridge, Massachusetts, USA; Department of Microbiology and Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Browning
authors.affiliation: Institute of Virology, Technische Universität München, Helmholz Zentrum, Munich, Germany; Institute of Surgical Pathology, University Hospital, Zurich, Switzerland.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Division of Nephrology, University Hospital, Zurich, Switzerland; Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland. Electronic address: Stephan.segerer@usz.ch.
authors.forename: Stephan
authors.initials: S
authors.lastname: Segerer
mesh_terms: D000328:Adult; D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005922:Glomerulonephritis, IGA / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000737:chemistry / Q000473:pathology; D007684:Kidney Tubules / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008181:Lupus Nephritis / Q000235:genetics / Q000378:metabolism*; D008214:Lymphocytes / Q000737:chemistry; D053259:Lymphotoxin beta Receptor / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D008233:Lymphotoxin-alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D053308:Lymphotoxin-beta / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis*; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome
chemical_list: D018925:Chemokines; D007136:Immunoglobulins; D008024:Ligands; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D012333:RNA, Messenger
keywords: chemokine; cytokine; glomerulonephritis; lupus