Phospholipase Cgamma1 suppresses foreign body giant cell formation by maintaining RUNX1 expression in macrophages

Abstract

Foreign body giant cell (FBGC) formation is associated with the inflammatory response following material implantation. However, the intracellular signaling events that regulate the process remain unclear. Here, we investigated the potential role of phospholipase C (PLC)gamma1, a crucial enzyme required for growth factor-induced signaling, on FBGC formation. Knock-down of PLCgamma1 using shRNA induced FBGC formation accompanied by increased expression of cathepsin K, DC-STAMP and CD36. Re-addition of PLCgamma1 decreased FBGC formation. PLCgamma1-deficiency caused a decrease in RUNX1 and subsequent PU.1 upregulation while subsequent rescue of RUNX1 in sh-PLCgamma1-transfected cells strongly inhibited FBGC formation. FBGC generated by knock-down of PLCgamma1 using shRNA resulted in strongly increased TNF-alpha production, with augmented activation of ERK, p38 MAPK and JNK, and subsequently NF-kappaB. Taken together, we suggest that PLCgamma1 plays a role in the foreign body response by regulating the RUNX1/PU.1/DC-STAMP axis in macrophages.