Regulatory properties of macrophages associated with alternative activation serve to limit the exaggerated inflammatory response during pneumonia caused by Pseudomonas aeruginosa infection. Arginase-1 is an important effector of these macrophages believed to play an essential role in decreasing injury and promoting repair. We investigated the role of arginase-1 in the control of inflammatory immune responses to P. aeruginosa pneumonia in mice that exhibit different immunologic phenotypes. C57BL/6 mice with conditional knockout of the arginase-1 (Arg1) gene from myeloid cells (Arg1^ΔM) or BALB/c mice treated with small molecule inhibitors of arginase were infected intratracheally with P. aeruginosa. Weight loss, mortality, bacterial clearance, and lung injury were assessed and compared, as were the characterization of immune cell populations over time post-infection. Myeloid arginase-1 deletion resulted in greater morbidity along with more severe inflammatory responses compared to littermate control mice. Arg1^ΔM mice had greater numbers of neutrophils, macrophages, and lymphocytes in their airways and lymph nodes compared to littermate controls. Additionally, Arg1^ΔM mice recovered from inflammatory lung injury at a significantly slower rate. Conversely, treatment of BALB/c mice with the arginase inhibitor S-(2-boronoethyl)-l-cysteine hydrochloride (BEC) did not change morbidity as defined by weight loss, but mice at day 10 post-infection treated with BEC had gained significantly more weight back than controls. Neutrophil and macrophage infiltration were similar between groups in the lung parenchyma, and neutrophil migration into the airways was reduced by BEC treatment. Differences seem to lie in the impact on T cell subset disposition. Arg1^ΔM mice had increased total CD4+ T cell expansion in the lymph nodes, and increased T cell activation, IFNγ production, and IL-17 production in the lymph nodes, lung interstitium, and airways, while treatment with BEC had no impact on T cell activation or IL-17 production, but reduced the number of T cells producing IFNγ in the lungs. Lung injury scores were increased in the Arg1^ΔM mice, but no differences were observed in the mice treated with pharmacologic arginase inhibitors. Overall, myeloid arginase production was demonstrated to be essential for control of damaging inflammatory responses associated with P. aeruginosa pneumonia in C57BL/6 mice, in contrast to a protective effect in the Th2-dominant BALB/c mice when arginase activity is globally inhibited.

与替代激活相关的巨噬细胞的调节特性有助于限制由铜绿假单胞菌感染引起的肺炎期间的过度炎症反应。Arginase-1 是这些巨噬细胞的重要效应物，被认为在减少损伤和促进修复方面发挥重要作用。我们研究了 arginase-1 在控制表现出不同免疫表型的小鼠对铜绿假单胞菌肺炎的炎症免疫反应中的作用。条件性敲除骨髓细胞中精氨酸酶-1 ( Arg1 ) 基因的 C57BL/6 小鼠 (Arg1 ^ΔM ) 或用精氨酸酶小分子抑制剂处理的 BALB/c 小鼠气管内感染铜绿假单胞菌. 评估和比较了体重减轻、死亡率、细菌清除率和肺损伤，以及感染后免疫细胞群随时间的表征。与同窝对照小鼠相比，髓样精氨酸酶 1 缺失导致更高的发病率以及更严重的炎症反应。与同窝对照相比， Arg1 ^ΔM小鼠的气道和淋巴结中有更多的中性粒细胞、巨噬细胞和淋巴细胞。此外，Arg1 ^ΔM小鼠从炎症性肺损伤中恢复的速度明显较慢。相反，用精氨酸酶抑制剂S -(2-boronoethyl) -l治疗 BALB/c 小鼠β-半胱氨酸盐酸盐 (BEC) 没有改变由体重减轻所定义的发病率，但在感染后第 10 天，用 BEC 治疗的小鼠体重比对照组明显增加。肺实质中各组的中性粒细胞和巨噬细胞浸润相似，BEC 治疗减少了中性粒细胞向气道的迁移。差异似乎在于对 T 细胞亚群分布的影响。Arg1 ^ΔM小鼠淋巴结中总 CD4+ T 细胞扩增增加，淋巴结、肺间质和气道中 T 细胞活化、IFNγ 产生和 IL-17 产生增加，而 BEC 治疗对 T 细胞没有影响活化或 IL-17 产生，但减少了肺中产生 IFNγ 的 T 细胞数量。Arg1 中的肺损伤评分增加^ΔM小鼠，但在用药理学精氨酸酶抑制剂治疗的小鼠中没有观察到差异。总体而言，骨髓精氨酸酶的产生被证明对于控制 C57BL/6 小鼠中与铜绿假单胞菌肺炎相关的破坏性炎症反应至关重要，而当精氨酸酶活性受到全局抑制时，这与 Th2 主导的 BALB/c 小鼠的保护作用形成鲜明对比。