Exosomes derived from TREM-2 knocked-out macrophages alleviated renal fibrosis via HSPa1b/AKT pathway.

Abstract

Macrophages are recognized as vital players in renal fibrosis, with a high degree of heterogeneity and plasticity, and the triggering receptor expressed on myeloid cell-2 (TREM-2) is highly expressed on macrophages and participates in the progression of tissue fibrosis. However, the mechanism by which TREM-2 mediates the progression of renal fibrosis is still unclear. Our study revealed that exosomes derived from TREM-2-deficient (TREM-2^-/-) macrophages suppressed the progression of fibrosis, as indicated by a greater matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) ratio at the protein level in secreted exosomes than in exosomes from wild-type (WT) macrophages in the fibrotic microenvironment. In addition, renal tubular epithelial cells (TECs) engulfed these nanoscale vesicles, and the expression of collagen I and α-smooth muscle actin (α-SMA) (a fibrosis-related marker) was obviously decreased. Through RNA-seq, we found that TREM-2^-/- macrophages increase the MMP-9/TIMP-1 ratio in their exosomes via the HSPa1b/AKT pathway. Notably, renal fibrosis was effectively alleviated in the obstructed kidneys of mice that received a renal pelvis injection of an adeno-associated virus (AAV-shTREM-2) containing the sequence used to silence TREM-2. However, VER-155008 (an inhibitor of HSPa1b) and Ly294002 (an inhibitor of AKT) reversed this effect. Moreover, polyclonal antibodies against TREM-2 also effectively relieved UUO-induced renal fibrosis. Overall, we validated that knocking down TREM-2 expression can inhibit the progression of renal fibrosis through a macrophage exosome-dependent pathway both in vitro and in vivo. Hence, our findings suggest that TREM-2 is a potential therapeutic target for CKD.