28: Mechanisms of triggering receptor expressed on myeloid cells-2 (TREM-2) regulation by transforming growth factor-β1 and interleukin-4; a new role for TREM-2 in matrix metalloproteinase regulation

Abstract

Triggering receptor expressed on myeloid cells (TREM)-2 is a receptor in the Ig superfamily, increased in inflammatory conditions such as allergy, multiple sclerosis and wound healing. In wound healing, TREM-2 is important for efficient repair and resolution of inflammation but how it is increased is unknown. Therefore, the aim of this project was to identify how TREM-2 is increased in inflammation and the functional effects of this. Transforming growth factor-β1 (TGF-β1) and interleukin-4 (IL-4) increased TREM-2 mRNA (p ⩽ 0.05) and protein expression in THP-1 cells, confirmed at the protein level in primary monocytes. IL-4 induced TREM-2 expression was unaffected by signal transducer and activator of transcription 6 (STAT-6) knockdown but inhibited by the phosphatidylinositol-3-kinase (PI3K) inhibitor LY-294002 (p ⩽ 0.01). TGF-β1 induced TREM-2 mRNA and protein expression were significantly reduced by the p38 MAP kinase inhibitor SB203580 (p ⩽ 0.001). The role of SMAD-3 and activating transcription factor 2 in this pathway are now being investigated. Interestingly, the ERK1/2 pathway inhibitor, PD98059 suppressed TGF-β1 induced TREM-2 expression at the protein level only, revealing an alternative pathway of regulation. To look at the functional effects of TREM-2 we measured the effect of TREM-2 siRNA knockdown on TGF-β1 induced IL-1β, IL-8 and matrix metalloproteinase −1 (MMP-1) mRNA in THP-1 cells. TREM-2 knockdown inhibited TGF-β1 induced MMP-1 mRNA by 73% (p ⩽ 0.001) but had no effect on the increase in IL-1β and IL-8. In conclusion, we show that IL-4 induces TREM-2 via a STAT-6 independent signalling pathway involving PI3K and identified TGF-β1 as a novel inducer of TREM-2. TGF-β1 induces TREM-2 through two mechanisms requiring p38 and ERK1/2 signalling pathways. IL-4 and TGF-β1 may be involved in increased TREM-2 expression seen in inflammatory disease. We also identify a new role for TREM-2 in the regulation of MMP-1 which may be how TREM-2 exerts its protective effects in wound healing.