Myeloid arginase-1 controls excessive inflammation and modulates T cell responses in Pseudomonas aeruginosa pneumonia.
Myeloid arginase-1 controls excessive inflammation and modulates T cell responses in Pseudomonas aeruginosa pneumonia.
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髓样精氨酸酶 1 控制铜绿假单胞菌肺炎中的过度炎症并调节 T 细胞反应。
DOI：
10.1016/j.imbio.2020.152034
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发表时间：
2021-01
期刊：
影响因子：
2.8
通讯作者：
Feola DJ
中科院分区：
文献类型：
--
作者：
Haydar D;Gonzalez R;Garvy BA;Garneau-Tsodikova S;Thamban Chandrika N;Bocklage TJ;Feola DJ
巨噬细胞的调节特性与交替激活有关，可用于限制铜绿假单胞菌感染引起的肺炎期间夸大的炎症反应。精氨酸酶-1是这些巨噬细胞的重要效应器，被认为在减轻损伤和促进修复方面发挥着重要作用。我们研究了精氨酸酶-1在不同免疫表型的小鼠铜绿假单胞菌肺炎炎症免疫反应中的作用。条件敲除精氨酸酶-1(Arg1-Δ-M)基因的C57BL/6小鼠和经精氨酸酶小分子抑制剂治疗的小鼠经气管内感染铜绿假单胞菌。评估和比较了体重减轻、死亡率、细菌清除和肺损伤，以及感染后一段时间内免疫细胞群体的特征。与产仔对照组小鼠相比，髓系精氨酸酶-1缺失导致更高的发病率和更严重的炎症反应。与同窝对照组相比，Arg1ΔM小鼠的呼吸道和淋巴结中性粒细胞、巨噬细胞和淋巴细胞数量较多。此外，Arg1ΔM小鼠从炎性肺损伤中恢复的速度明显较慢。反之，用精氨酸酶抑制剂S-(2-硼乙基)-L-半胱氨酸盐酸盐(BEC)治疗BALB/c小鼠并没有改变体重减轻所定义的发病率，但在感染后第10天，BEC治疗的小鼠体重显著增加。中性粒细胞和巨噬细胞在肺实质的浸润相似，中性粒细胞向呼吸道的迁移被BEC处理后减少。不同之处似乎在于对T细胞亚群的影响。Arg1ΔM小鼠的T细胞总数增加，淋巴结、肺间质和呼吸道的T细胞活化、干扰素γ产生和IL-17产生增加，而BEC治疗对T细胞活化和IL-17产生无影响，但减少肺中产生干扰素γ的T细胞数量。Arg1ΔM组小鼠肺损伤评分增加，但用药物精氨酸酶抑制剂治疗的小鼠肺损伤评分无明显差异。总体而言，髓系精氨酸酶的产生被证明对于控制与铜绿假单胞菌肺炎相关的破坏性炎症反应是必不可少的，而在Th2占优势的BALB/c小鼠中，当精氨酸酶活性被全局抑制时，精氨酸酶的保护作用相反。
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 (Arg1ΔM) 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. Arg1ΔM mice had greater numbers of neutrophils, macrophages, and lymphocytes in their airways and lymph nodes compared to littermate controls. Additionally, Arg1ΔM 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. Arg1ΔM 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 Arg1ΔM 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.
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影响因子：
4.9
作者：
Feola, David J.;Garvy, Beth A.;Murphy, Brian S.
通讯作者：
Murphy, Brian S.
影响因子：
168.9
作者：
Equi, A;Balfour-Lynn, IM;Rosenthal, M
通讯作者：
Rosenthal, M
影响因子：
4.4
作者：
Haydar, Dalia;Cory, Theodore J.;Feola, David J.
通讯作者：
Feola, David J.
影响因子：
4
作者：
El-Bassossy, Hany M.;El-Fawal, Rania;Fahmy, Ahmed
通讯作者：
Fahmy, Ahmed
DOI：
10.4049/jimmunol.0902009
发表时间：
2010-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Herbert DR;Orekov T;Roloson A;Ilies M;Perkins C;O'Brien W;Cederbaum S;Christianson DW;Zimmermann N;Rothenberg ME;Finkelman FD
通讯作者：
Finkelman FD