生分解性マイクロ粒子はサイズ依存的およびmTOR依存的なプロセスを通じて抗炎症性の自然免疫記憶を促進する

Emerging evidence demonstrates that innate immune cells can maintain a non-specific memory, not only in response to microbe-associated ligands such as β-glucan, but also synthetic biomaterials and nano- and microparticles. This creates an opportunity to leverage biomaterials which can establish favourable innate immune responses and memory for therapeutic applications. In this study, we identify particle size as a critical physical determinant influencing both acute macrophage activation and long-term innate immune memory. Specifically, biodegradable poly(lactic-co-glycolic acid) particles in the 1-2 µm size range promoted an anti-inflammatory phenotype and enhanced oxidative phosphorylation in bone marrow-derived macrophages, through a process dependent on mTOR signalling. In contrast to the well documented pro-inflammatory innate immune training seen with microbial stimuli such as β-glucans, exposure of macrophages to 1-2um poly(lactic-co-glycolic acid) particles promoted a durable anti-inflammatory reprogramming, marked by elevated IL-10 and IL-1 receptor antagonist secretion upon secondary stimulation, and metabolic re-wiring. Moreover, bone marrow from mice injected with PLGA particles in this size range, were reprogrammed to upregulate IL-1Ra and IL-10 secretion upon a re-stimulation, which persisted up to one week post-injection. These findings uncover how the physicochemical properties of polymeric nanoparticles differentially modulate innate immune cells and regulate the induction of innate training.