美国科罗拉多大学Eric M. Pietras课题组发现，一种独特的代谢和表观遗传状，态诱导了自身免疫小鼠造血干细胞衍生巨噬细胞的训练免疫（TI）。相关论文于2024年10月15日发表在《细胞—干细胞》杂志上。

研究人员探究了长期造血干细胞（HSCs^LT）在慢性自身免疫性疾病中对训练免疫（TI）的影响。通过使用系统性红斑狼疮（SLE）小鼠模型，研究发现来源于自身免疫性小鼠的骨髓巨噬细胞（BMDMs）表现出TI的标志性特征，包括分枝杆菌杀伤力增强和炎性细胞因子的产生，这与糖酵解代谢增加有联系。

研究表明，来源于自身免疫小鼠的造血干细胞构成了一个可移植的、长期存在的巨噬细胞储库，这些巨噬细胞具有TI的功能特性。

然而，这些BMDMs表现出糖酵解活性和代谢基因染色质可及性降低，同时与TI相关转录调控因子的表达仍保持升高。因此，暴露于自身免疫炎症的造血干细胞可产生巨噬细胞，其中TI的功能和代谢特性是分离的。该研究数据支持这样一个模型，即TI的特征是一系列由分子和代谢状态诱导的免疫功能增强。

附：英文原文

Title: A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice

Author: Taylor S. Mills, Bailee Kain, Matt A. Burchill, Etienne Danis, Erin D. Lucas, Rachel Culp-Hill, Courtney M. Cowan, Wolfgang E. Schleicher, Sweta B. Patel, Brandon T. Tran, Ruoqiong Cao, Andrew Goodspeed, Sarah Ferrara, Shaun Bevers, Beth A. Jirón Tamburini, James R. Roede, Angelo D’Alessandro, Katherine Y. King, Eric M. Pietras

Issue&Volume: 2024-10-15

Abstract: Here, we investigate the contribution of long-term hematopoietic stem cells (HSCsLT) to trained immunity (TI) in the setting of chronic autoimmune disease. Using a mouse model of systemic lupus erythematosus (SLE), we show that bone marrow-derived macrophages (BMDMs) from autoimmune mice exhibit hallmark features of TI, including increased Mycobacterium avium killing and inflammatory cytokine production, which are mechanistically linked to increased glycolytic metabolism. We show that HSCs from autoimmune mice constitute a transplantable, long-term reservoir for macrophages that exhibit the functional properties of TI. However, these BMDMs exhibit reduced glycolytic activity and chromatin accessibility at metabolic genes while retaining elevated expression of TI-associated transcriptional regulators. Hence, HSC exposed to autoimmune inflammation can give rise to macrophages in which the functional and metabolic properties of TI are decoupled. Our data support a model in which TI is characterized by a spectrum of molecular and metabolic states driving augmented immune function.

DOI: 10.1016/j.stem.2024.09.010

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00324-2