Early IL-17A production helps establish Mycobacterium intracellulare infection in mice.
Early IL-17A production helps establish Mycobacterium intracellulare infection in mice.
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DOI：
10.1371/journal.ppat.1010454
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发表时间：
2022-04
期刊：
影响因子：
6.7
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中科院分区：
文献类型：
--
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非结核分枝杆菌（NTM）感染常见于结构性肺损伤患者。为了研究NTM感染是如何建立并引起肺损伤的，我们通过鼻内接种临床分离的胞内支原体建立了NTM小鼠模型。在39周的感染过程中，细菌在肺部持续生长，导致进行性肉芽肿和纤维化肺损伤，死亡率超过50%。肺中性粒细胞在感染后1周明显增加，感染后2周减少，感染后39周再次增加。IL-17A在感染后1-2周升高，感染后3周降低。感染早期（0-2周）和晚期（32-34周）中性粒细胞的消耗对慢性感染小鼠的死亡率或肺损伤没有影响。然而，在早期感染期间，IL-17A的中和可显著降低慢性感染小鼠的细菌负担、纤维化肺损伤和死亡率。由于已知IL-17A调节基质金属蛋白酶（MMPs），并且MMPs参与肺纤维化的发病机制，因此我们测定了胞内支原体感染小鼠肺中MMPs的水平。有趣的是，抗il - 17a中和抗体显著降低了MMP-3。此外，体外数据显示，外源性IL-17A在M.胞内感染时，会增加肺上皮细胞产生MMP-3。总之，我们的研究结果表明，早期IL-17A的产生先于并促进小鼠有组织的肺分枝杆菌细胞内感染，至少部分是通过MMP-3的产生。为了确定非结核分枝杆菌（NTM）感染是如何建立的以及NTM疾病是如何发展的，我们通过鼻内接种细胞内分枝杆菌（NTM患者中最常见的分离菌株之一）建立了慢性NTM小鼠模型。这种细菌在肺部持续生长，造成纤维化肺损伤，在39周内死亡率超过50%。感染早期（1-2周）肺中性粒细胞和IL-17A迅速增加，感染后39周再次出现中性粒细胞。在早期（0-2周）和慢性（32-34周）感染期间，中性粒细胞的消耗对慢性感染小鼠的死亡率或肺损伤没有影响。在感染早期（0-2周）中和IL-17A可显著降低感染后39周的死亡率、细菌负担、纤维化肺损伤和肺基质金属蛋白酶(MMP)-3。外源性IL-17A在M.胞内感染时增加肺上皮细胞产生MMP-3，而不是MMP-9。本研究表明，早期IL-17A的产生有助于小鼠细胞内感染。
Nontuberculous mycobacteria (NTM) infection is common in patients with structural lung damage. To address how NTM infection is established and causes lung damage, we established an NTM mouse model by intranasal inoculation of clinical isolates of M. intracellulare. During the 39-week course of infection, the bacteria persistently grew in the lung and caused progressive granulomatous and fibrotic lung damage with mortality exceeding 50%. Lung neutrophils were significantly increased at 1 week postinfection, reduced at 2 weeks postinfection and increased again at 39 weeks postinfection. IL-17A was increased in the lungs at 1–2 weeks of infection and reduced at 3 weeks postinfection. Depletion of neutrophils during early (0–2 weeks) and late (32–34 weeks) infection had no effect on mortality or lung damage in chronically infected mice. However, neutralization of IL-17A during early infection significantly reduced bacterial burden, fibrotic lung damage, and mortality in chronically infected mice. Since it is known that IL-17A regulates matrix metalloproteinases (MMPs) and that MMPs contribute to the pathogenesis of pulmonary fibrosis, we determined the levels of MMPs in the lungs of M. intracellulare-infected mice. Interestingly, MMP-3 was significantly reduced by anti-IL-17A neutralizing antibody. Moreover, in vitro data showed that exogenous IL-17A exaggerated the production of MMP-3 by lung epithelial cells upon M. intracellulare infection. Collectively, our findings suggest that early IL-17A production precedes and promotes organized pulmonary M. intracellulare infection in mice, at least in part through MMP-3 production. To determine how nontuberculous mycobacteria (NTM) infection is established and how NTM disease progresses, we established a chronic NTM mouse model by intranasal inoculation of M. intracellulare, one of the most frequently isolated strains in NTM patients. The bacteria persistently grew in the lungs and caused fibrotic lung damage with over 50% mortality over 39 weeks. Neutrophils and IL-17A rapidly increased in the lung during early (1–2 weeks) infection, and neutrophils reappeared at 39 weeks postinfection. Depletion of neutrophils during early (0–2 weeks) and chronic (32–34 weeks) infection had no effect on mortality or lung damage in chronically infected mice. Neutralization of IL-17A during early (0–2 weeks) infection significantly reduced mortality, bacterial burden, fibrotic lung damage, and lung matrix metalloproteinase (MMP)-3 at 39 weeks postinfection. Exogenous IL-17A exaggerated the production of MMP-3, but not MMP-9, by lung epithelial cells upon M. intracellulare infection. This study demonstrates that early IL-17A production contributes to established M. intracellulare infection in mice.
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影响因子：
3.7
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