Decreased expression of ADAM10 on monocytes is associated with chronic allograft dysfunction in kidney transplant...

Chronic allograft dysfunction (CAD) is a common cause of allograft loss in kidney transplant recipients (KTRs). Our previous study found that elevated serum soluble T cell immunoglobulin mucin-3 (sTim-3) was positively associated with the severity of CAD in KTRs. sTim-3 was reported to be generated from ADAM10/ADAM17-mediated ectodomain shedding of membrane Tim-3 (mTim-3) in humans. However, whether mTim-3 shedding-related molecules participate in the progression of CAD remains unknown. Here, we explored the relationships between different forms of Tim-3, including mTim-3 on different peripheral blood cell subsets, serum and urine sTim-3, and ADAM10/17 expression and active status to investigate their roles in CAD.

63 KTRs with stable grafts, 91 KTRs with CAD and 42 healthy controls (HCs) were enrolled. Total Tim-3, pADAM10/17 and mADAM10/17 proteins were semiquantified by western blot. Serum and urine sTim-3 concentrations were determined by ELISA. mTim-3 and ADAM10/17 expression on leukocyte subpopulations was determined by flow cytometry.

The KTR groups displayed significantly higher levels of urine sTim-3 pg/μmol creatinine than the HC group, while no difference was found between the two KTR groups. KTRs with CAD presented reduced nonactive pADAM10 protein but unaltered active mADAM10 when compared to the Stable group; no difference was found between the KTR groups regarding total Tim-3 and p/m ADAM17 protein levels. In addition, the CAD group showed lower mTim-3 expression on BDCA3⁺ DC than the Stable group; no other difference was observed in its expression on B, T, NK, NKT, monocyte subsets and other DC subsets among groups. With the deterioration of allograft function, ADAM10 expression densities on classical, intermediate, and non-classical monocytes were significantly decreased. Correlation analyses revealed that eGFR and serum sTim-3 exhibited weak to modest correlations with ADAM10 on monocyte and DC subsets.

Our data indicated that ADAM10, especially its decreased expression on monocytes, may play an important role in the progression of CAD in KTRs. However, whether there is an interaction between ADAM10 and mTim-3 in the pathogenesis of CAD in KTRs needs to be further studied.