Inflammatory Responses Reprogram TREGS Through Impairment of Neuropilin-1

Abstract

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 .

Adiponectin-expressing Treg facilitate T lymphocyte development in thymic nurse cell complexes

“…The loss-of-Treg stability leads to immune-mediated diseases 35 . Impairment of Nrp1 facilitates the reprograming of Treg 53 . By contrast, semaphorin-Nrp1 signaling axis acts to maintain Treg stability 54 .…”

Role of Neuropilin 1 in COVID-19 Patients with Acute Ischemic Stroke

“…Moreover, the chronic inflammatory process negatively regulates and controls NRP-1 to induce Treg cells instability with the activation of TH17 cells. Thus, chronic inflammatory disorders trigger the reprogramming of Treg cells toward TH17 cells via the NRP-1-dependent pathway [ 74 ]. Taken together, the high NRP-1 serum level could be a compensatory mechanism to repress inflammatory and immunological instabilities ( Figure 5 ).…”

Pyroptosis in Periprosthetic Osteolysis

“…Apparently, these inflammatory responses are mainly related to the phagocytosis of wear particles by macrophages/monocytes [ 22 ]. Micro/nano-scale wear particles activate a wide variety of periprosthetic cell types, such as osteoblasts, lymphocytes, fibroblasts, multinucleated foreign-body giant cells and macrophages [ 17 , 18 , 19 , 23 ], to secrete pro-inflammatory mediators along with chemotaxis factors, including tumor necrosis factor-alpha (TNF-α), macrophage colony-stimulating factor (M-CSF), interleukin (IL)-1β, IL-6, IL-17A [ 24 ], prostaglandin E2 (PGE2), vascular endothelial growth factor (VEGF) and RANKL [ 25 , 26 , 27 ] etc., which further drive osteoclast formation, differentiation and maturation, shifting bone metabolic homeostasis to osteolysis, ultimately leading to periprosthetic bone resorption and osteolysis [ 28 , 29 ]. AL secondary to PPO can be defined as a failure of the implant due to poor initial fixation and mechanical damage to fixation over time or biological loss of fixation instigated by immunological reactions to wear particles [ 30 ].…”