sTREM2 Differentially Affects Cytokine Expression in Myeloid-Derived Cell Models via MAPK–JNK Signaling Pathway.

Simple Summary: TREM2 is a critical innate immune receptor belonging to the immunoglobulin superfamily and plays an important role in regulating the function of innate immune cells, such as microglia and macrophages. TREM2 mutations or dysregulation of TREM2 signaling are associated with the risk of neurodegenerative diseases, such as Alzheimer's disease. sTREM2 is a soluble form of TREM2 shed from the cell surface TREM2 receptor and has a short half-life (~4 h), but its roles still remain largely uncharacterized. Our study has found that sTREM2 can induce the expression of inflammatory cytokines in THP-1 monocytes during the time course from 2 to 8 h but up-regulates the expression of anti-inflammatory cytokines at later time points. sTREM2 has differential effects on cytokine expression in macrophages with more stimulating effects on M0 macrophages, less of an effect on M2 macrophages, and some inhibitory effects on M1 macrophages at early time-points. Characterization of several signaling pathways found that sTREM2-mediated cytokine expression mainly occurs via MAPK–JNK signaling in cells. Our study suggests that sTREM2 has differential effects on cytokine expression in THP-1 monocytes and macrophages and that MAPK–JNK signaling is mainly involved in sTREM2-mediated cytokine expression in cells. TREM2 is a critical innate immune receptor primarily expressed on myeloid-derived cells, such as microglia and macrophages. Mutations in TREM2 are linked to several neurodegenerative diseases including Alzheimer's disease (AD). TREM2 can be cleaved from the cell membrane and released as soluble TREM2 (sTREM2). sTREM2 levels are shown to peak prior to AD, with its levels fluctuating throughout disease progression. However, the mechanism by which sTREM2 may affect innate immune responses is largely uncharacterized. In this study, we investigated whether sTREM2 can induce inflammatory response in myeloid-derived THP-1 monocytes and macrophages and characterized the signaling mechanisms involved. Our results show that sTREM2 was capable of stimulating the expression of several inflammatory cytokines in THP-1 cells throughout the time course of 2 h to 8 h but inducing anti-inflammatory cytokine expression at later time points. A TREM2 antibody was capable of inhibiting the expression of some cytokines induced by sTREM2 but enhancing others. The complex of sTREM2/TREM2 antibody was shown to enhance IL-1β expression, which was partially blocked by an NLRP3 specific inhibitor, indicating that the complex activated the NRLP3 inflammasome pathway. sTREM2 was also shown to have differential effects on cytokine expression in M0, M1, and M2 macrophages differentiated from THP-1 cells. sTREM2 has a more stimulating effect on cytokine expression in M0 macrophages, less of an effect on M2 macrophages, and some inhibitory effects on cytokine expression in M1 macrophages at early time points. Analyses of several signaling pathways revealed that sTREM2-induced expression of cytokines occurs mainly through MAPK–JNK signaling. Our work reveals differential effects of sTREM2 on cytokine expression profiles of THP-1 cells and macrophages and demonstrates that the MAPK–JNK signaling pathway is mainly responsible for sTREM2-induced cytokine expression. [ABSTRACT FROM AUTHOR]