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
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
PLoS One. 2013 Dec 16;8(12):e82498. doi: 10.1371/journal.pone.0082498. eCollection 2013.
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.
肾小管间质损伤是慢性肾病中的常见表现，其特征为持续的炎症和纤维化，进而导致肾功能障碍和终末期肾病。肾脏损伤时，内源性配体可被释放，被天然免疫传感器识别，从而激活天然免疫系统。一类新的天然免疫传感器是髓样细胞触发受体（TREM）家族。TREM1是一种激活受体，需要与跨膜衔接分子DAP12（DNAX相关蛋白12）结合才能进行细胞信号传导。TREM1-DAP12途径与几种Toll样受体（TLR）的细胞内信号通路存在相互作用，能够放大TLR信号，从而加重炎症程度。到目前为止，多项研究表明TLR在梗阻性肾病中发挥作用，但TREM1-DAP12在此过程中的作用尚不清楚。因此，我们研究了TREM1在人类和小鼠进行性肾病中的表达，并通过将野生型（WT）、TREM1/3双敲除和DAP12敲除小鼠用于小鼠单侧输尿管梗阻（UUO）模型，进一步探究TREM1-DAP12的作用。在肾积水患者的肾组织中观察到了TREM1阳性细胞。我们发现，在WT小鼠的肾脏中，UUO后DAP12 mRNA、TREM1 mRNA和蛋白水平升高。与WT小鼠相比，DAP12敲除小鼠在UUO进展过程中肾脏MCP-1、KC和TGF-β1水平较低，巨噬细胞浸润较少，而TREM1/3双敲除小鼠的肾脏MCP-1水平较低。WT、TREM1/3双敲除和DAP12敲除小鼠的肾纤维化程度相当。我们得出结论，DAP12部分通过TREM1/3参与了UUO进展过程中的肾脏炎症。
