Division of Hematology and Oncology, Department of Internal Medicine, Nihon University School of Medicine, 30-1 Ohyaguchi-kami-cho, Itabashi-ku, Tokyo, 173-8610, Japan.
Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki, Japan.
Ann Hematol. 2023 Dec;102(12):3311-3323. doi: 10.1007/s00277-023-05425-w. Epub 2023 Sep 1.
Hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome, is caused by the incessant activation of lymphocytes and macrophages, resulting in damage to organs, including hematopoietic organs. Recently, we demonstrated that repeated lipopolysaccharide (LPS) treatment induces HLH-like features in senescence-accelerated (SAMP1/TA-1) mice but not in senescence-resistant control (SAMR1) mice. Hematopoietic failure in LPS-treated SAMP1/TA-1 mice was attributed to hematopoietic microenvironment dysfunction, concomitant with severely imbalanced M1 and M2 macrophage polarization. Macrophages are a major component of the bone marrow (BM) hematopoietic microenvironment. Clodronate liposomes are useful tools for in vivo macrophage depletion. In this study, we depleted macrophages using clodronate liposomes to determine their role in the hematopoietic microenvironment in SAMP1/TA-1 and SAMR1 mice. Under clodronate liposome treatment, the response between SAMR1 and SAMP1/TA-1 mice differed as follows: (1) increase in the number of activated M1 and M2 macrophages derived from newly generated macrophages and M2-dominant and imbalanced M1 and M2 macrophage polarization in the BM and spleen; (2) severe anemia and thrombocytopenia; (3) high mortality rate; (4) decrease in erythroid progenitors and B cell progenitors in the BM; and (5) decrease in the mRNA expression of erythroid-positive regulators such as erythropoietin and increase in that of erythroid- and B lymphoid-negative regulators such as interferon-γ in the BM. Depletion of residual macrophages in SAMP1/TA-1 mice impaired hematopoietic homeostasis, particularly erythropoiesis and B lymphopoiesis, owing to functional impairment of the hematopoietic microenvironment accompanied by persistently imbalanced M1/M2 polarization. Thus, macrophages play a vital role in regulating the hematopoietic microenvironment to maintain homeostasis.
噬血细胞性淋巴组织细胞增生症（HLH）是一种炎症过度活跃的综合征，由淋巴细胞和巨噬细胞的持续激活引起，导致包括造血器官在内的器官损伤。最近，我们证明，重复给予脂多糖（LPS）可在衰老加速（SAMP1/TA-1）小鼠中诱导出类 HLH 特征，但在衰老抵抗对照（SAMR1）小鼠中不会。LPS 处理的 SAMP1/TA-1 小鼠中的造血衰竭归因于造血微环境功能障碍，同时伴有 M1 和 M2 巨噬细胞极化的严重失衡。巨噬细胞是骨髓（BM）造血微环境的主要组成部分。氯膦酸脂质体是体内巨噬细胞耗竭的有用工具。在这项研究中，我们使用氯膦酸脂质体耗竭巨噬细胞，以确定它们在 SAMP1/TA-1 和 SAMR1 小鼠造血微环境中的作用。在氯膦酸脂质体处理下，SAMR1 和 SAMP1/TA-1 小鼠之间的反应如下：（1）来自新生成的巨噬细胞的激活的 M1 和 M2 巨噬细胞数量增加，以及 BM 和脾脏中 M2 优势和不平衡的 M1 和 M2 巨噬细胞极化；（2）严重贫血和血小板减少；（3）高死亡率；（4）BM 中红系祖细胞和 B 细胞祖细胞减少；（5）BM 中红系阳性调节剂如促红细胞生成素的 mRNA 表达减少，而红系和 B 淋巴系阴性调节剂如干扰素-γ的表达增加。由于造血微环境功能障碍伴持续不平衡的 M1/M2 极化，SAMP1/TA-1 小鼠中残留巨噬细胞的耗竭损害了造血稳态，特别是红细胞生成和 B 淋巴生成。因此，巨噬细胞在调节造血微环境以维持稳态方面发挥着重要作用。
