title: Role of TREM1-DAP12 in renal inflammation during obstructive nephropathy.
abstract: Tubulo-interstitial damage is a common finding in the chronically diseased kidney and is characterized by ongoing inflammation and fibrosis leading to renal dysfunction and end-stage renal disease. Upon kidney injury, endogenous ligands can be released which are recognized by innate immune sensors to alarm innate immune system. A new family of innate sensors is the family of TREM (triggering receptor expressed on myeloid cell). TREM1 is an activating receptor and requires association with transmembrane adapter molecule DAP12 (DNAX-associated protein 12) for cell signaling. TREM1-DAP12 pathway has a cross-talk with intracellular signaling pathways of several Toll-like receptors (TLRs) and is able to amplify TLR signaling and thereby contributes to the magnitude of inflammation. So far, several studies have shown that TLRs play a role in obstructive nephropathy but the contribution of TREM1-DAP12 herein is unknown. Therefore, we studied TREM1 expression in human and murine progressive renal diseases and further investigated the role for TREM1-DAP12 by subjecting wild-type (WT), TREM1/3 double KO and DAP12 KO mice to murine unilateral ureter obstruction (UUO) model. In patients with hydronephrosis, TREM1 positive cells were observed in renal tissue. We showed that in kidneys from WT mice, DAP12 mRNA and TREM1 mRNA and protein levels were elevated upon UUO. Compared to WT mice, DAP12 KO mice displayed less renal MCP-1, KC and TGF-β1 levels and less influx of macrophages during progression of UUO, whereas TREM1/3 double KO mice displayed less renal MCP-1 level. Renal fibrosis was comparable in WT, TREM1/3 double KO and DAP12 KO mice. We conclude that DAP12, partly through TREM1/3, is involved in renal inflammation during progression of UUO.
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tammaro
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Stroo
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Elena
authors.initials: E
authors.lastname: Rampanelli
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Froilan
authors.initials: F
authors.lastname: Blank
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Loes M
authors.initials: LM
authors.lastname: Butter
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Nike
authors.initials: N
authors.lastname: Claessen
authors.affiliation: Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takai
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jaklien C
authors.initials: JC
authors.lastname: Leemans
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands ; Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Dessing
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018450:Disease Progression; D005260:Female; D006801:Humans; D006869:Hydronephrosis / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; C110546:TYROBP protein, human; D053773:Transforming Growth Factor beta1; D000073871:Triggering Receptor Expressed on Myeloid Cells-1