Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL

Qin, Hao; Shetty, Sreerama; Tucker, Torry A.; Idell, Steven; Tang, Hua

doi:10.3390/cells11030563

Cited by 14 publications

(17 citation statements)

References 80 publications

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“…In normal lung tissue, low TLR4 expression ensures a controlled state of inflammation. In Contrast, in Spn-infected patients, increased expression of TLR4 is sustained, resulting in inappropriate signaling by lung epithelial cells to LPS, through activating various molecules including MyD88, which ultimately activates the NF-κB signaling pathway and boosts the excessive release of TNF-α and other pro-inflammatory cytokines, resulting in the blood-gas barrier damage and lung epithelial cell apoptosis ( Aboudounya and Heads, 2021 ; Tang et al., 2021 ; Hao et al., 2022 ). In this study, as the serum levels of pro-inflammatory cytokines and endotoxin were increased, the expressions of ZO-1, Claudin 5 and Occludin in the lung tissues of Spn-infected mice were significantly decreased while TLR4, p38 and NF-κB were increased.…”

Section: Discussionmentioning

confidence: 99%

Cephalosporins-induced intestinal dysbiosis exacerbated pulmonary endothelial barrier disruption in streptococcus pneumoniae-infected mice

Wang

Shi

Ying

2022

Front. Cell. Infect. Microbiol.

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Antibiotic abuse is growing more severe in clinic, and even short-term antibiotic treatment can cause long-term gut dysbiosis, which may promote the development and aggravation of diseases. Cephalosporins as the broad-spectrum antibiotics are widely used for prevention and treatment of community-acquired respiratory tract infection in children. However, their potential consequences in health and disease have not been fully elaborated. In this study, the effects of cefaclor, cefdinir and cefixime on intestinal microbiota and lung injury were investigated in Streptococcus pneumoniae (Spn)-infected mice. The results showed that the proportion of coccus and bacillus in intestinal microbiota were changed after oral administration with cefaclor, cefdinir and cefixime twice for 10 days, respectively. Compared with the Spn-infected group, the proportion of Bifidobacterium and Lactobacillus in intestine were significantly reduced, while Enterococcus and Candida was increased after cephalosporin treatment. Furthermore, 3 cephalosporins could obviously increase the number of total cells, neutrophils and lymphocytes in BALF as well as the serum levels of endotoxin, IL-2, IL-1β, IL-6 and TNF-α. Mechanically, cephalosporins accelerated Spn-induced pulmonary barrier dysfunction via mediating the mRNA expressions of endothelial barrier-related proteins (Claudin 5, Occludin, and ZO-1) and inflammation-related proteins (TLR4, p38 and NF-κB). However, all of those consequences could be partly reversed by Bifidobacterium bifidum treatment, which was closely related to the elevated acetate production, indicating the protective effects of probiotic against antibiotic-induced intestinal dysbiosis. Therefore, the present study demonstrated that oral administration with cephalosporins not only disrupted intestinal microecological homeostasis, but also increased the risk of Spn infection, resulting in severer respiratory inflammation and higher bacterial loads in mice.

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Section: Discussionmentioning

confidence: 99%

Cephalosporins-induced intestinal dysbiosis exacerbated pulmonary endothelial barrier disruption in streptococcus pneumoniae-infected mice

Wang

Shi

Ying

2022

Front. Cell. Infect. Microbiol.

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“…However, IFN-γ is a very dangerous double-edged sword, because IFN-γ can also induce severe damage to airway epithelial cells and pneumocytes, including cellular death [ 40 , 41 ]. One study identified an interferon (IFN)-γ-regulated subset of monocytes, CCR2 + monocytes, as a major cause of acute lung injury (ALI) during influenza A (IAV) virus infections, where IFN-γ regulated the recruitment of the inflammatory phenotype of CCR2 + monocytes [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…CD8 + T-cells were the main sources of IFN-γ in IAV-infected lungs, and IFN-γ had a signaling role in the regulation of CCR2 + monocyte-mediated lung pathology during IAV infections [ 40 ]. Furthermore, IFN-γ not only attracts lung damaging, inflammatory monocytes, IFN-γ can also cause pneumocyte death by necroptosis [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

A mammalian lung's immune system minimizes tissue damage by initiating five major sequential phases of defense

Roe

2023

Clin Exp Med

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The mammalian lungs encounter several pathogens, but have a sophisticated multi-phase immune defense. Furthermore, several immune responses to suppress pulmonary pathogens can damage the airway epithelial cells, particularly the vital alveolar epithelial cells (pneumocytes). The lungs have a sequentially activated, but overlapping, five phase immune response to suppress most pathogens, while causing minimal damage to the airway epithelial cells. Each phase of the immune response may suppress the pathogens, but if the previous phase proves inadequate, a stronger phase of immune response is activated, but with an increased risk of airway epithelial cell damage. The first phase immune response involves the pulmonary surfactants, which have proteins and phospholipids with potentially sufficient antibacterial, antifungal and antiviral properties to suppress many pathogens. The second phase immune response involves the type III interferons, having pathogen responses with comparatively minimal risk of damage to airway epithelial cells. The third phase immune response involves type I interferons, which implement stronger immune responses against pathogens with an increased risk of damage to airway epithelial cells. The fourth phase immune response involves the type II interferon, interferon-γ, which activates stronger immune responses, but with considerable risk of airway epithelial cell damage. The fifth phase immune response involves antibodies, potentially activating the complement system. In summary, five major phases of immune responses for the lungs are sequentially initiated to create an overlapping immune response which can suppress most pathogens, while usually causing minimal damage to the airway epithelial cells, including the pneumocytes.

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“…During influenza virus infection, the monocytes/macrophages are recruited from the cycle into the damaged areas of lung tissues to repair the injury and clear the virus, producing and releasing a variety of factors, including proinflammatory cytokines (TNF- α , IL-1 β , and IL-6), antiviral cytokines (IFN- α / γ ) and chemokines (MCP-1), which are directly or indirectly involved in the antiviral response. The immune response induced by these mediators is beneficial to the organism, but if induced excessively, it can be transformed into an immunopathological response, causing destruction of self-cells and inflammatory damage to lung tissues [ 5 , 33 – 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…e immune response induced by these mediators is beneficial to the organism, but if induced excessively, it can be transformed into an immunopathological response, causing destruction of self-cells and inflammatory damage to lung tissues [5,[33][34][35].…”

Section: Discussionmentioning

confidence: 99%

Lignans from Mosla scabra Ameliorated Influenza A Virus-Induced Pneumonia via Inhibiting Macrophage Activation

Cai

Zhang

2022

Evidence-Based Complementary and Alternative Medicine

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The lower respiratory tract infection, induced by influenza virus, coronaviruses, and respiratory syncytial virus, remains a serious threat to human health that can cause a global pandemic. Thus, finding effective chemicals and therapeutic measures to advance the functional restoration of the respiratory tract after infection has been the emphasis of the studies on the subjects. Mosla scabra is a natural medicinal plant used for treating various lung and gastrointestinal diseases, including viral infection, cough, chronic obstructive pulmonary disease, acute gastroenteritis, and diarrhoea. In this study, the antiviral and anti-inflammatory effects of total lignans (MSTL) extracted from the plant were investigated in influenza A virus (IAV)-infected mice and RAW 264.7 macrophages. MSTL could not only protect the macrophages against IAV-induced pyroptosis but also could lighten the lung inflammation induced by IAV in vivo and in vitro. The network pharmacology analysis revealed that differentially expressed genes, mainly involving in EGFR tyrosine kinase inhibitor resistance, endocrine resistance, HIF-1 signaling pathway, C-type lectin receptor signaling pathway, and FOXO signaling pathway, contributed to the IAV-induced alveolar macrophage dysfunction. It indicated that MSTL enhanced the function of alveolar macrophages and improved IAV-induced lung injury in mice.

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Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL

Cited by 14 publications

References 80 publications

Cephalosporins-induced intestinal dysbiosis exacerbated pulmonary endothelial barrier disruption in streptococcus pneumoniae-infected mice

Cephalosporins-induced intestinal dysbiosis exacerbated pulmonary endothelial barrier disruption in streptococcus pneumoniae-infected mice

A mammalian lung's immune system minimizes tissue damage by initiating five major sequential phases of defense

Lignans from Mosla scabra Ameliorated Influenza A Virus-Induced Pneumonia via Inhibiting Macrophage Activation

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