Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China; Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell. 2022 May 12;185(10):1709-1727.e18. doi: 10.1016/j.cell.2022.03.043. Epub 2022 Apr 27.
Bone marrow (BM)-mediated trained innate immunity (TII) is a state of heightened immune responsiveness of hematopoietic stem and progenitor cells (HSPC) and their myeloid progeny. We show here that maladaptive BM-mediated TII underlies inflammatory comorbidities, as exemplified by the periodontitis-arthritis axis. Experimental-periodontitis-related systemic inflammation in mice induced epigenetic rewiring of HSPC and led to sustained enhancement of production of myeloid cells with increased inflammatory preparedness. The periodontitis-induced trained phenotype was transmissible by BM transplantation to naive recipients, which exhibited increased inflammatory responsiveness and disease severity when subjected to inflammatory arthritis. IL-1 signaling in HSPC was essential for their maladaptive training by periodontitis. Therefore, maladaptive innate immune training of myelopoiesis underlies inflammatory comorbidities and may be pharmacologically targeted to treat them via a holistic approach.
骨髓（BM）介导的训练性固有免疫（TII）是造血干细胞和祖细胞（HSPC）及其髓系前体细胞的免疫应答增强状态。我们在这里表明，适应性 BM 介导的 TII 是炎症合并症的基础，牙周炎-关节炎轴就是一个例子。实验性牙周炎相关的全身炎症会导致 HSPC 的表观遗传重排，并导致具有更高炎症准备能力的髓系细胞的持续增强产生。牙周炎诱导的训练表型可通过 BM 移植传递给未致敏的受体，当这些受体受到炎症性关节炎的影响时，它们会表现出更高的炎症反应性和疾病严重程度。HSPC 中的 IL-1 信号对于它们被牙周炎的适应性训练是必需的。因此，髓系发生的适应性固有免疫训练是炎症合并症的基础，并且可以通过整体治疗方法通过药理学靶向来治疗它们。
