TREM-1 regulates macrophage phenotypes and kidney injury in unilateral ureteral obstruction mice model

• Main Authors: Tze-Han Luo, 駱子翰
• Other Authors: Der-Cherng Tarng
• Format: Others
• Language: en_US
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/81905690851134609067

碩士 === 國立陽明大學 === 生理學研究所 === 99 === Monocyte-derived macrophage infiltration of kidney interstitium is a common pathogenic feature of chronic kidney disease (CKD). Distinct classically (M1) and alternatively (M2) activated macrophages have been synonymous with tissue injury and repair, respectively. Cumulative data have demonstrated that triggering receptor expressed on myeloid cells-1 (TREM-1) is a novel receptor constitutively expressed on most monocytes/macrophages. In the present study, we elucidated as to whether TREM-1 involves in renal inflammatory reaction and contributes to diverse macrophages phenotype transition. In vivo, mice of unilateral ureteral obstruction (UUO), a well-established CKD model, were used to explore the mechanism of progression of renal failure. The mRNA levels of TREM-1 up-regulated significantly at 7 and 14 d after UUO. We further performed UUO in TREM-1-/- mice to assess the potential role of TREM-1 in renal inflammation. In TREM-1-/- mice, tubular injury and interstitial collagen deposition were significantly decreased in UUO renal cortex stained with periodic acid-Schiff (PAS) and Masson trichrome as compared to WT mice, despite a similar infiltration of F4/80-positive macrophages between these two groups. In analyzing the markers of mRNA expression for activated macrophages after UUO, we found that inducible nitric oxide synthase (M1 markers) and pro-inflammatory cytokines like TNF-α, IL-1β and IL-6 were significantly decreased, and arginase-1, MR, Ym1 and IL-10 (M2 markers) mRNA expression were significantly increased in TREM-1-/- mice. We hypothesized that after UUO-injured kidney would contain an unknown TREM-1 ligand(s) which may mediate, notably in monocytes/macrophages, the M1 versus M2 polarization. Bone marrow-derived macrophages (BMDM) were obtained from bone marrow of femurs of WT or TREM-1-/- male mice and differentiated with macrophage colony stimulating factor (M-CSF) in vitro. Interesting, co-incubating soluble tissue lysates prepared from UUO-affected WT kidneys triggered M1 differentiation in WT bone marrow-derived macrophages but not in TREM-1 KO cells in vitro. Furthermore, in the study of neutralization, modulation of the expression of GM-CSF and IFN-gamma in BMDM by WT UUO 14 d soluble tissue lysates treatment which promote characteristics of M1 macrophages by production of iNOS. Correspondingly, clinical analysis on specimens collected from UUO nephritis patients also demonstrated a strong correlation between TREM-1 expression, macrophage infiltration, iNOS levels and the severity of renal damage. In summary, TREM-1 is a crucial factor induced in UUO nephritis which contributes to the pathogenic inflammation through the induction of type I macrophage differentiation.