University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, LabEx LipSTIC, Besançon, France.
MED'INN'Pharma, Besançon, France.
Front Immunol. 2022 Oct 28;13:1021413. doi: 10.3389/fimmu.2022.1021413. eCollection 2022.
Several chronic inflammatory diseases are associated with non-resolving inflammation. Conventional anti-inflammatory drugs fail to completely cure these diseases. Resolution pharmacology is a new therapeutic approach based on the use of pro-resolving mediators that accelerate the resolution phase of inflammation by targeting the productive phase of inflammation. Indeed, pro-resolving mediators prevent leukocyte recruitment and induce apoptosis of accumulated leukocytes. This approach is now called resolution therapy with the introduction of complex biological drugs and cell-based therapies. The main objective of resolution therapy is to specifically reduce the duration of the resolution phase to accelerate the return to homeostasis. Under physiological conditions, macrophages play a critical role in the resolution of inflammation. Indeed, after the removal of apoptotic cells (a process called efferocytosis), macrophages display anti-inflammatory reprogramming and subsequently secrete multiple pro-resolving factors. These factors can be used as resolution therapy. Here, we review the different mechanisms leading to anti-inflammatory reprogramming of macrophages after efferocytosis and the pro-resolving factors released by these efferocytic macrophages. We classify these mechanisms in three different categories: macrophage reprogramming induced by apoptotic cell-derived factors, by molecules expressed by apoptotic cells (., "eat-me" signals), and induced by the digestion of apoptotic cell-derived materials. We also evoke that macrophage reprogramming may result from cooperative mechanisms, for instance, implicating the apoptotic cell-induced microenvironment (including cellular metabolites, specific cytokines or immune cells). Then, we describe a new drug candidate belonging to this resolution therapy. This candidate, called SuperMApo, corresponds to the secretome of efferocytic macrophages. We discuss its production, the pro-resolving factors present in this drug, as well as the results obtained in experimental models of chronic (e.g., arthritis, colitis) and acute (e.g., peritonitis or xenogeneic graft--host disease) inflammatory diseases.
几种慢性炎症性疾病与无法解决的炎症有关。传统的抗炎药物无法完全治愈这些疾病。解决药理学是一种新的治疗方法，基于使用促解决介质，通过靶向炎症的生产阶段来加速炎症的解决阶段。实际上，促解决介质可防止白细胞募集并诱导积累的白细胞凋亡。随着复杂的生物药物和基于细胞的疗法的引入，这种方法现在被称为解决疗法。解决疗法的主要目标是专门缩短解决阶段的持续时间，以加速恢复到体内平衡。在生理条件下，巨噬细胞在炎症的解决中起着关键作用。实际上，在清除凋亡细胞（称为吞噬作用的过程）后，巨噬细胞表现出抗炎重编程，随后分泌多种促解决因子。这些因子可用作解决疗法。在这里，我们综述了吞噬作用后导致巨噬细胞抗炎重编程的不同机制以及这些吞噬作用巨噬细胞释放的促解决因子。我们将这些机制分为三类：凋亡细胞衍生因子诱导的巨噬细胞重编程、凋亡细胞表达的分子（例如，“吃我”信号）诱导的巨噬细胞重编程和由凋亡细胞衍生材料的消化诱导的巨噬细胞重编程。我们还提到，巨噬细胞重编程可能源自协同机制，例如涉及凋亡细胞诱导的微环境（包括细胞代谢物、特定细胞因子或免疫细胞）。然后，我们描述了一种属于这种解决疗法的新药物候选物。该候选物称为 SuperMApo，对应于吞噬作用巨噬细胞的分泌组。我们讨论了它的生产、这种药物中存在的促解决因子以及在慢性（例如关节炎、结肠炎）和急性（例如腹膜炎或异种移植物宿主疾病）炎症模型中获得的结果。
