Myeloid arginase-1 controls excessive inflammation and modulates T cell responses in Pseudomonas aeruginosa pneumonia
| Autor: | Sylvie Garneau-Tsodikova, Rene Gonzalez, Beth A. Garvy, Dalia Haydar, Thèrése Bocklage, David J. Feola, Nishad Thamban Chandrika |
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| Rok vydání: | 2021 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male 0301 basic medicine Myeloid Neutrophils T cell Immunology Inflammation Lung injury Lymphocyte Activation Article Immunomodulation Mice 03 medical and health sciences 0302 clinical medicine Immune system T-Lymphocyte Subsets Pneumonia Bacterial Animals Humans Immunology and Allergy Medicine Genetic Predisposition to Disease Pseudomonas Infections ARG1 Lung Th1-Th2 Balance Mice Knockout Mice Inbred BALB C Arginase business.industry Hematology Macrophage Activation Boronic Acids Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Pseudomonas aeruginosa Cytokines Female Lymph medicine.symptom business Genetic Background 030215 immunology |
| Zdroj: | Immunobiology |
| ISSN: | 0171-2985 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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