Lasola Jackline Joy Martín, Cottingham Andrea L, Scotland Brianna L, Truong Nhu, Hong Charles C, Shapiro Paul, Pearson Ryan M
Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 W. Baltimore Street, Baltimore, MD 21201, USA.
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine Street, Baltimore, MD 21201, USA.
Pharmaceutics. 2021 Nov 2;13(11):1841. doi: 10.3390/pharmaceutics13111841.
Inflammation is a key homeostatic process involved in the body's response to a multitude of disease states including infection, autoimmune disorders, cancer, and other chronic conditions. When the initiating event is poorly controlled, severe inflammation and globally dysregulated immune responses can occur. To address the lack of therapies that efficaciously address the multiple aspects of the dysregulated immune response, we developed cargo-less immunomodulatory nanoparticles (iNPs) comprised of poly(lactic acid) (PLA) with either poly(vinyl alcohol) (PVA) or poly(ethylene-alt-maleic acid) (PEMA) as stabilizing surfactants and investigated the mechanisms by which they exert their inherent anti-inflammatory effects. We identified that iNPs leverage a multimodal mechanism of action by physically interfering with the interactions between pathogen-associated molecular patterns (PAMPs) and bone marrow-derived macrophages (BMMΦs). Additionally, we showed that iNPs mitigate proinflammatory cytokine secretions induced by LPS via a time- and composition-dependent abrogation of NF-κB p65 and p38 MAPK activation. Lastly, inhibition studies were performed to establish the role of a pH-sensing G-protein-coupled receptor, GPR68, on contributing to the activity of iNPs. These data provide evidence for the multimodal mechanism of action of iNPs and establish their potential use as a novel therapeutic for the treatment of severe inflammation.
炎症是一种关键的稳态过程，参与机体对多种疾病状态的反应，包括感染、自身免疫性疾病、癌症和其他慢性疾病。当初始事件控制不佳时，可能会发生严重炎症和整体免疫反应失调。为了解决缺乏有效治疗失调免疫反应多个方面的疗法的问题，我们开发了无载药免疫调节纳米颗粒（iNPs），其由聚乳酸（PLA）与聚乙烯醇（PVA）或聚（乙烯-alt-马来酸）（PEMA）作为稳定表面活性剂组成，并研究了它们发挥固有抗炎作用的机制。我们发现iNPs通过物理干扰病原体相关分子模式（PAMPs）与骨髓来源巨噬细胞（BMMΦs）之间的相互作用，利用多模式作用机制。此外，我们表明iNPs通过时间和成分依赖性消除NF-κB p65和p38 MAPK激活，减轻LPS诱导的促炎细胞因子分泌。最后，进行抑制研究以确定pH敏感G蛋白偶联受体GPR68在促进iNPs活性中的作用。这些数据为iNPs的多模式作用机制提供了证据，并确立了它们作为治疗严重炎症的新型疗法的潜在用途。
