Role of TREM1-DAP12 in renal inflammation during obstructive nephropathy

• Published in: PloS one 2013-12, Vol.8 (12), p.e82498-e82498
• Main Authors: Tammaro, Alessandra, Stroo, Ingrid, Rampanelli, Elena, Blank, Froilan, Butter, Loes M, Claessen, Nike, Takai, Toshiyuki, Colonna, Marco, Leemans, Jaklien C, Florquin, Sandrine, Dessing, Mark C
• Format: Article
• Language: English
• Subjects: Adapters; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antigens; Bone morphogenetic proteins; Chronic kidney failure; DAP12 protein; Disease; Disease Progression; Edema; End-stage renal disease; Female; Fibrosis; Hostages; Humans; Hydronephrosis - metabolism; Hydronephrosis - pathology; Immune system; Immunoglobulins; Immunology; Inflammation; Inflammation - metabolism; Inflammation - pathology; Innate immunity; Intracellular signalling; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kidney transplantation; Kidneys; Ligands; Macrophages; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Messenger RNA; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocyte chemoattractant protein 1; mRNA; Nephropathy; Neutrophils; Pathology; Proteins; Receptors; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Renal function; Rodents; Sensors; Signal transduction; Toll-like receptors; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Transforming growth factors; Transplants & implants; Triggering Receptor Expressed on Myeloid Cells-1; Ureter; Ureteral Obstruction - metabolism; Ureteral Obstruction - pathology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0082498

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.