TREM-1 regulates macrophage polarization in ureteral obstruction

Abstract

Chronic kidney disease (CKD) is an emerging worldwide public health problem. Inflammatory cell infiltration and activation during the early stages in injured kidneys is a common pathologic feature of CKD. Here, we determined whether an important inflammatory regulator, triggering receptor expressed on myeloid cells (TREM)-1, is upregulated in renal tissues collected from mouse ureteral obstruction-induced nephritis. TREM-1 is crucial for modulating macrophage polarization, and has a pivotal role in mediating tubular injury and interstitial collagen deposition in obstructive nephritis. Lysates from nephritic kidneys triggered a TREM-1-dependent M1 polarization ex vivo, consistent with the observation that granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived M1 macrophages express higher levels of TREM-1 in comparison with M-CSF-derived cells. Moreover, agonistic TREM-1 cross-link significantly strengthens the inductions of iNOS and GM-CSF in M1 cells. These observations are validated by a strong clinical correlation between infiltrating TREM-1-expressing/iNOS-positive macrophages and renal injury in human obstructive nephropathy. Thus, TREM-1 may be a potential diagnostic and therapeutic target in human kidney disease.