Matrix metalloproteinase-9 deficiency protects mice from severe influenza A viral infection

Rojas, Joselyn; Wang, Xiaoyun; Tipper, Jennifer L.; Burkett, Patrick R.; Zúñiga, Joaquı́n; Ashtekar, Amit R.; Polverino, Francesca; Rout, Amit; Yambayev, Ilyas; Hernández, Carmen; Jiménez, Luís Carlos Villamil; Ramírez, Gustavo; Harrod, Kevin S.; Owen, Caroline A.

doi:10.1172/jci.insight.99022

Cited by 39 publications

(33 citation statements)

References 82 publications

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“…Conversely, MMP3 has a detrimental role in mouse models of acute lung injury and pulmonary fibrosis, with MMP3-deficient mice exhibiting less severe lung injury and protection from bleomycin-induced fibrosis (Warner et al, 2001;Yamashita et al, 2011). Although further studies are required to elucidate the roles of MMPs in respiratory viral infections, it has been shown in a mouse model of severe influenza infection (IAV) that MMP9 −/− mice exhibited increased survival and were protected from IAV-induced lung injury (Rojas-Quintero et al, 2018). This suggests that a reduction in MMP9 expression would be beneficial in host defence against respiratory viral infections.…”

Section: Discussionmentioning

confidence: 99%

Neurturin regulates the lung-resident macrophage inflammatory response to viral infection

et al. 2020

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Lung-resident macrophages are crucial to the maintenance of health and in the defence against lower respiratory tract infections. Macrophages adapt to local environmental cues that drive their appropriate function; however, this is often dysregulated in many inflammatory lung pathologies. In mucosal tissues, neuro-immune interactions enable quick and efficient inflammatory responses to pathogenic threats. Although a number of factors that influence the antimicrobial response of lung macrophages are known, the role of neuronal factors is less well understood. Here, we show an intricate circuit involving the neurotrophic factor, neurturin (NRTN) on human lung macrophages that dampens pro-inflammatory cytokine release and modulates the type of matrix metalloproteinases produced in response to viral stimuli. This circuit involves type 1 interferon–induced up-regulation of RET that when combined with the glial cell line-derived neurotrophic factor (GDNF) receptor α2 (GFRα2) allows binding to epithelial-derived NRTN. Our research highlights a non-neuronal immunomodulatory role for NRTN and a novel process leading to a specific antimicrobial immune response by human lung-resident macrophages.

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Section: Discussionmentioning

confidence: 99%

Neurturin regulates the lung-resident macrophage inflammatory response to viral infection

et al. 2020

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“…Towards this end, a report found that inhibition of the collagenase MT1-MMP (MMP14) limited tissue damage and improved survival in a mouse model of severe influenza virus infection and in a model of influenza-pneumococcal coinfection [14]. Targeting the downstream effects of inflammation and immune-associated lung damage may be a viable means of limiting influenza-associated pathology [15].…”

Section: How Influenza Triggers Ardsmentioning

confidence: 99%

Influenza virus-related critical illness: pathophysiology and epidemiology

2019

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Influenza virus affects the respiratory tract by direct viral infection or by damage from the immune system response. In humans, the respiratory epithelium is the only site where the hemagglutinin (HA) molecule is effectively cleaved, generating infectious virus particles. Virus transmission occurs through a susceptible individual’s contact with aerosols or respiratory fomites from an infected individual. The inability of the lung to perform its primary function of gas exchange can result from multiple mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity from direct epithelial cell killing, and degradation of the critical extracellular matrix. Approximately 30–40% of hospitalized patients with laboratory-confirmed influenza are diagnosed with acute pneumonia. These patients who develop pneumonia are more likely to be < 5 years old, > 65 years old, Caucasian, and nursing home residents; have chronic lung or heart disease and history of smoking, and are immunocompromised. Influenza can primarily cause severe pneumonia, but it can also present in conjunction with or be followed by a secondary bacterial infection, most commonly by Staphylococcus aureus and Streptococcus pneumoniae . Influenza is associated with a high predisposition to bacterial sepsis and ARDS. Viral infections presenting concurrently with bacterial pneumonia are now known to occur with a frequency of 30–50% in both adult and pediatric populations. The H3N2 subtype has been associated with unprecedented high levels of intensive care unit (ICU) admission. Influenza A is the predominant viral etiology of acute respiratory distress syndrome (ARDS) in adults. Risk factors independently associated with ARDS are age between 36 and 55 years old, pregnancy, and obesity, while protective factors are female sex, influenza vaccination, and infections with Influenza A (H3N2) or Influenza B viruses. In the ICU, particularly during the winter season, influenza should be suspected not only in patients with typical symptoms and epidemiology, but also in patients with severe pneumonia, ARDS, sepsis with or without bacterial co-infection, as well as in patients with encephalitis, myocarditis, and rhabdomyolysis.

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“…Pharmacological inhibition of MMP-9 also has been reported to partially reduce lung pathology in mice caused by in uenza virus, and MMP-9 de ciency protects mice from severe in uenza A viral infection [30,31]. An in vitro study showed that in uenza virus infection increases MMP-9 secretion and promoter activity in Vero cells [33].…”

Section: Discussionmentioning

confidence: 99%

“…Our data showed that an increase of MMP-9 in the lung immunohistochemical analysis of the model and the sham group on day 6 after infection, and a remarkable decrease in Gua Sha treatment. Recently, Joselyn et al showed that the increasing pulmonary adaptive immune response to IAV, with higher CD4 + T lymphocytes and lower frequencies of anti-in ammatory Tregs, appeared in MMP-9 -/mice after IAV infection [31]. And MMP-9 might decrease IL-17 production in the lungs by selectively inhibiting IL-23 expression [32].…”

Section: Discussionmentioning

confidence: 99%

Gua Sha attenuates the pulmonary inflammation in mice infected with PR8 virus by balancing the ratio of Treg/Th17

Li¹,

Wang²,

Kong³

et al. 2020

Preprint

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Background: Gua Sha, an ancient Chinese treatment which produces the pressure on the skin, is used to prevent and treat cold for thousands of years. There’re evidences to approve that it can activate immune response and reduce the inflammation. However, how it has the effect on T helper 17 cells (Th17) and regulatory T cells (Treg) is poorly understood. Here, this study aims at the relationship between the pressure-stoke in the skin and pulmonary Th17 as well as Treg in PR8-infected mice. Methods: ICR mice were randomly divided into five groups. The body weight and survival rates of all groups were monitored through the experiment. At the end of experiment, lung inflammation was detected by HE staining and the expression of Matrix metalloproteinase-9 (MMP-9) was measured by immunohistochemistry. Th17 and Treg from lung tissues was analyzed by flow cytometry. esults: Our results indicated that the survival rates of prophylactic and therapeutic group respectively showed 20% and 10% though Gua Sha treatment didn’t restore the weight-loss of PR8-infected mice. What’s more important, Gua Sha remarkably inhibited inflammatory infiltration and the expression of MMP-9 of lung tissues in infected mice ( p ＜0.05). Finally, the ratio of Treg/Th17 from lung tissues in PR8-infected mice was significantly increased as compared with control mice while Gua Sha treatment remarkably inhibited this enhancement. All these results indicated that Gua Sha has the efficacy on reducing the pulmonary inflammation in PR8-infected mice possibly via restoring the Treg/Th17 balance. Conclusions: Our findings for the first time suggest that Gua Sha exhibits a significant inhibition of inflammatory infiltration with down-regulation of MMP-9 in lung tissues from RR8-infected mice, which might be associated with the differentiation of Th17 and Treg. Further research will be carried toward how Gua Sha functions on maintaining the homeostasis of Th17 and Treg in the lungs.

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Matrix metalloproteinase-9 deficiency protects mice from severe influenza A viral infection

Cited by 39 publications

References 82 publications

Neurturin regulates the lung-resident macrophage inflammatory response to viral infection

Neurturin regulates the lung-resident macrophage inflammatory response to viral infection

Influenza virus-related critical illness: pathophysiology and epidemiology

Gua Sha attenuates the pulmonary inflammation in mice infected with PR8 virus by balancing the ratio of Treg/Th17

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