IL-6 Prevents Lung Macrophage Death and Lung Inflammation Injury by Inhibiting GSDME- and GSDMD-Mediated Pyroptosis during Pneumococcal Pneumosepsis
ABSTRACT Streptococcus pneumoniae is a leading bacterial cause of a wide range of infections, and pneumococcal pneumosepsis causes high mortality in hosts infected with antibiotic-resistant strains and those who cannot resolve ongoing inflammation. The factors which influence the development and out...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2022-04-01
|
| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.02049-21 |
| _version_ | 1828491686999752704 |
|---|---|
| author | Xuemei Gou Wenchun Xu Yusi Liu Yang Peng Wenlong Xu Yibing Yin Xuemei Zhang |
| author_facet | Xuemei Gou Wenchun Xu Yusi Liu Yang Peng Wenlong Xu Yibing Yin Xuemei Zhang |
| author_sort | Xuemei Gou |
| collection | DOAJ |
| description | ABSTRACT Streptococcus pneumoniae is a leading bacterial cause of a wide range of infections, and pneumococcal pneumosepsis causes high mortality in hosts infected with antibiotic-resistant strains and those who cannot resolve ongoing inflammation. The factors which influence the development and outcome of pneumosepsis are currently unclear. IL-6 is critical for maintaining immune homeostasis, and we determined that this cytokine is also essential for resisting pneumosepsis, as it inhibits macrophage pyroptosis and pyroptosis-related inflammation injury in the lung. IL-6 affected infection outcomes in mice and exerted a protective role, primarily via macrophages. We further found that IL-6 deficiency led to increased lung macrophage death and aggravated lung inflammation, and that exogenous administration of IL-6 protein could decrease macrophage death and alleviate lung tissue inflammation. IL-6 also protected Streptococcus pneumoniae-induced lung macrophage death and lung inflammation injury by inhibiting gasdermin E (GSDME)- and gasdermin D (GSDMD)-mediated pyroptosis. Together, these data reveal a novel mechanism for the development of pneumosepsis and the critical protective role of IL-6. These findings may assist in the early identification and treatment of pneumococcal pneumosepsis. IMPORTANCE Pneumococcal pneumonia has been a significant cause of morbidity and mortality throughout human history. Failing to control pneumococcal pneumonia and resolve ongoing inflammation in a host can cause sepsis, namely pneumococcal pneumosepsis, and death ensues. Few theories have suggested an optimally therapeutic option for this infectious disease. The interleukin-6 (IL-6, a cytokine featuring pleiotropic activity) theory, proposed here, implies that IL-6 acts as a protector against pneumococcal pneumosepsis. IL-6 prevents lung macrophage death and lung inflammation injury by inhibiting a caspase-3-GSDME-mediated switch from apoptosis to pyroptosis and inhibiting caspase-1-GSDMD-mediated classic pyroptosis during pneumococcal pneumosepsis. Thus, IL-6 is an important determinant for controlling bacterial invasion and a homeostatic coordinator of pneumococcal pneumosepsis. This study clarifies a novel mechanism of occurrence and development of pneumonia and secondary sepsis following a Streptococcus pneumoniae infection. It is important for the early identification and treatment of pneumococcal pneumosepsis. |
| first_indexed | 2024-12-11T11:07:06Z |
| format | Article |
| id | doaj.art-a0e000d515024748b4ca0549b5055186 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-12-11T11:07:06Z |
| publishDate | 2022-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-a0e000d515024748b4ca0549b50551862022-12-22T01:09:40ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972022-04-0110210.1128/spectrum.02049-21IL-6 Prevents Lung Macrophage Death and Lung Inflammation Injury by Inhibiting GSDME- and GSDMD-Mediated Pyroptosis during Pneumococcal PneumosepsisXuemei Gou0Wenchun Xu1Yusi Liu2Yang Peng3Wenlong Xu4Yibing Yin5Xuemei Zhang6Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, ChinaKey Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, ChinaDepartment of Laboratory Medicine, First Hospital of China Medical University, Shenyang, ChinaKey Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, ChinaKey Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, ChinaKey Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, ChinaKey Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, ChinaABSTRACT Streptococcus pneumoniae is a leading bacterial cause of a wide range of infections, and pneumococcal pneumosepsis causes high mortality in hosts infected with antibiotic-resistant strains and those who cannot resolve ongoing inflammation. The factors which influence the development and outcome of pneumosepsis are currently unclear. IL-6 is critical for maintaining immune homeostasis, and we determined that this cytokine is also essential for resisting pneumosepsis, as it inhibits macrophage pyroptosis and pyroptosis-related inflammation injury in the lung. IL-6 affected infection outcomes in mice and exerted a protective role, primarily via macrophages. We further found that IL-6 deficiency led to increased lung macrophage death and aggravated lung inflammation, and that exogenous administration of IL-6 protein could decrease macrophage death and alleviate lung tissue inflammation. IL-6 also protected Streptococcus pneumoniae-induced lung macrophage death and lung inflammation injury by inhibiting gasdermin E (GSDME)- and gasdermin D (GSDMD)-mediated pyroptosis. Together, these data reveal a novel mechanism for the development of pneumosepsis and the critical protective role of IL-6. These findings may assist in the early identification and treatment of pneumococcal pneumosepsis. IMPORTANCE Pneumococcal pneumonia has been a significant cause of morbidity and mortality throughout human history. Failing to control pneumococcal pneumonia and resolve ongoing inflammation in a host can cause sepsis, namely pneumococcal pneumosepsis, and death ensues. Few theories have suggested an optimally therapeutic option for this infectious disease. The interleukin-6 (IL-6, a cytokine featuring pleiotropic activity) theory, proposed here, implies that IL-6 acts as a protector against pneumococcal pneumosepsis. IL-6 prevents lung macrophage death and lung inflammation injury by inhibiting a caspase-3-GSDME-mediated switch from apoptosis to pyroptosis and inhibiting caspase-1-GSDMD-mediated classic pyroptosis during pneumococcal pneumosepsis. Thus, IL-6 is an important determinant for controlling bacterial invasion and a homeostatic coordinator of pneumococcal pneumosepsis. This study clarifies a novel mechanism of occurrence and development of pneumonia and secondary sepsis following a Streptococcus pneumoniae infection. It is important for the early identification and treatment of pneumococcal pneumosepsis.https://journals.asm.org/doi/10.1128/spectrum.02049-21IL-6macrophageinflammationpyroptosispneumococcal pneumosepsis |
| spellingShingle | Xuemei Gou Wenchun Xu Yusi Liu Yang Peng Wenlong Xu Yibing Yin Xuemei Zhang IL-6 Prevents Lung Macrophage Death and Lung Inflammation Injury by Inhibiting GSDME- and GSDMD-Mediated Pyroptosis during Pneumococcal Pneumosepsis Microbiology Spectrum IL-6 macrophage inflammation pyroptosis pneumococcal pneumosepsis |
| title | IL-6 Prevents Lung Macrophage Death and Lung Inflammation Injury by Inhibiting GSDME- and GSDMD-Mediated Pyroptosis during Pneumococcal Pneumosepsis |
| title_full | IL-6 Prevents Lung Macrophage Death and Lung Inflammation Injury by Inhibiting GSDME- and GSDMD-Mediated Pyroptosis during Pneumococcal Pneumosepsis |
| title_fullStr | IL-6 Prevents Lung Macrophage Death and Lung Inflammation Injury by Inhibiting GSDME- and GSDMD-Mediated Pyroptosis during Pneumococcal Pneumosepsis |
| title_full_unstemmed | IL-6 Prevents Lung Macrophage Death and Lung Inflammation Injury by Inhibiting GSDME- and GSDMD-Mediated Pyroptosis during Pneumococcal Pneumosepsis |
| title_short | IL-6 Prevents Lung Macrophage Death and Lung Inflammation Injury by Inhibiting GSDME- and GSDMD-Mediated Pyroptosis during Pneumococcal Pneumosepsis |
| title_sort | il 6 prevents lung macrophage death and lung inflammation injury by inhibiting gsdme and gsdmd mediated pyroptosis during pneumococcal pneumosepsis |
| topic | IL-6 macrophage inflammation pyroptosis pneumococcal pneumosepsis |
| url | https://journals.asm.org/doi/10.1128/spectrum.02049-21 |
| work_keys_str_mv | AT xuemeigou il6preventslungmacrophagedeathandlunginflammationinjurybyinhibitinggsdmeandgsdmdmediatedpyroptosisduringpneumococcalpneumosepsis AT wenchunxu il6preventslungmacrophagedeathandlunginflammationinjurybyinhibitinggsdmeandgsdmdmediatedpyroptosisduringpneumococcalpneumosepsis AT yusiliu il6preventslungmacrophagedeathandlunginflammationinjurybyinhibitinggsdmeandgsdmdmediatedpyroptosisduringpneumococcalpneumosepsis AT yangpeng il6preventslungmacrophagedeathandlunginflammationinjurybyinhibitinggsdmeandgsdmdmediatedpyroptosisduringpneumococcalpneumosepsis AT wenlongxu il6preventslungmacrophagedeathandlunginflammationinjurybyinhibitinggsdmeandgsdmdmediatedpyroptosisduringpneumococcalpneumosepsis AT yibingyin il6preventslungmacrophagedeathandlunginflammationinjurybyinhibitinggsdmeandgsdmdmediatedpyroptosisduringpneumococcalpneumosepsis AT xuemeizhang il6preventslungmacrophagedeathandlunginflammationinjurybyinhibitinggsdmeandgsdmdmediatedpyroptosisduringpneumococcalpneumosepsis |