Inflammatory Responses Reprogram T(REGS) Through Impairment of Neuropilin-1

Chronic inflammatory insults compromise immune cell responses and ultimately contribute to pathologic outcomes. Clinically, it has been suggested that bone debris and implant particles, such as polymethylmethacrylate (PMMA), which are persistently released following implant surgery evoke heightened immune, inflammatory, and osteolytic responses that contribute to implant failure. However, the precise mechanism underlying this pathologic response remains vague. T(REGS), the chief immune-suppressive cells, express the transcription factor Foxp3 and are potent inhibitors of osteoclasts. Using an intra-tibial injection model, we show that PMMA particles abrogate the osteoclast suppressive function of T(REGS). Mechanistically, PMMA particles induce T(REG) instability evident by reduced expression of Foxp3. Importantly, intra-tibial injection of PMMA initiates an acute innate immune and inflammatory response, yet the negative impact on T(REGS) by PMMA remains persistent. We further show that PMMA enhance T(H)17 response at the expense of other T effector cells (T(EFF)), particularly T(H)1. At the molecular level, gene expression analysis showed that PMMA particles negatively regulate Nrp-1/Foxo3a axis to induce T(REG) instability, to dampen T(REG) activity and to promote phenotypic switch of T(REGS) to T(H)17 cells. Taken together, inflammatory cues and danger signals, such as bone and implant particles exacerbate inflammatory osteolysis in part through reprogramming T(REGS).