Roles of TREM2 in degeneration of human nucleus pulposus cells via NF-κB p65.

Abstract

Nuclear factor (NF)-κB p65 plays a key role in the development of intervertebral disc degeneration (IDD). Herein, we found that messenger RNA levels of human triggering receptor expressed on myeloid cells-2 (TREM2) and NF-κB p65 were upregulated and strongly positive correlated (r2 = 0.299, P = 0.0126) in nucleus pulposus (NP) tissues of patients with IDD. To investigate the role of TREM2 in the development of IDD and whether NF-κB p65 was the underlying mechanism, whereby TREM2 played its role, we established TREM2-siRNA-transfected human degenerative NP cells and TREM2-overexpression vector-transfected human normal NP cells. Degeneration of human NP cells was assessed by measuring cell apoptosis, cell proliferation, and the secretion of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. Protein levels of Bcl2, Bax, total NF-κB p65 in whole cell lysates, cytoplasm NF-κB p65, and nuclear NF-κB p65 were determined to evaluate underlying mechanisms. Our data elucidated that TREM2 silencing was a therapy for human degenerative NP cells through inhibiting cell apoptosis, promoting cell proliferation, suppressing production of tumor necrosis factor-α, IL 1β, and IL-6, and the mechanisms included decreasing Bax while enhancing Bcl2, downregulating total NF-κB p65, and retarding NF-κB p65 nuclear translocation. On the contrary, upregulated TREM2 showed the opposite effects, accelerating the degeneration of human normal NP cells. Downregulating TREM2 and total NF-κB p65 and inhibiting NF-κB p65 nucleus translocation were also confirmed in NP tissue samples of four IDD rats. We concluded that TREM2 functioned as a promoter in the degeneration of human NP cells. Downregulating TREM2 may be a novel therapeutic strategy for human IDD.