TLR4 regulates ROS and autophagy to control neutrophil extracellular traps formation against Streptococcus pneumoniae in acute otitis media

Dong, Yilin; Jin, Chunfang; Ding, Zhiqiang; Zhu, Yiting; He, Qian; Zhang, Xinxin; Ai, Rongshuang; Yin, Yibing; He, Yujuan

doi:10.1038/s41390-020-0964-9

Cited by 23 publications

(20 citation statements)

References 38 publications

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“…The activation of autophagy promotes the clearance of B. cenocepacia 12 , Legionella pneumophila 18 , Listeria monocytogenes 73 , and Mycobacterium tuberculosis 74 . Increased mROS production which activates autophagy improves the clearance of Mycobacterium tuberculosis 75 , Streptococcus pneumoniae 76 and Listeria monocytogenes 77 . Here, we found that autophagy is defective in gsdmd −/− mice and their derived macrophages.…”

Section: Lc3i Lc3iimentioning

confidence: 99%

Gasdermin D restricts Burkholderia cenocepacia infection in vitro and in vivo

Estfanous

Krause

Anne

et al. 2021

Sci Rep

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Burkholderia cenocepacia (B. cenocepacia) is an opportunistic bacterium; causing severe life threatening systemic infections in immunocompromised individuals including cystic fibrosis patients. The lack of gasdermin D (GSDMD) protects mice against endotoxin lipopolysaccharide (LPS) shock. On the other hand, GSDMD promotes mice survival in response to certain bacterial infections. However, the role of GSDMD during B. cenocepacia infection is not yet determined. Our in vitro study shows that GSDMD restricts B. cenocepacia replication within macrophages independent of its role in cell death through promoting mitochondrial reactive oxygen species (mROS) production. mROS is known to stimulate autophagy, hence, the inhibition of mROS or the absence of GSDMD during B. cenocepacia infections reduces autophagy which plays a critical role in the restriction of the pathogen. GSDMD promotes inflammation in response to B. cenocepacia through mediating the release of inflammasome dependent cytokine (IL-1β) and an independent one (CXCL1) (KC). Additionally, different B. cenocepacia secretory systems (T3SS, T4SS, and T6SS) contribute to inflammasome activation together with bacterial survival within macrophages. In vivo study confirmed the in vitro findings and showed that GSDMD restricts B. cenocepacia infection and dissemination and stimulates autophagy in response to B. cenocepacia. Nevertheless, GSDMD promotes lung inflammation and necrosis in response to B. cenocepacia without altering mice survival. This study describes the double-edged functions of GSDMD in response to B. cenocepacia infection and shows the importance of GSDMD-mediated mROS in restriction of B. cenocepacia.

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Section: Lc3i Lc3iimentioning

confidence: 99%

Gasdermin D restricts Burkholderia cenocepacia infection in vitro and in vivo

Estfanous

Krause

Anne

et al. 2021

Sci Rep

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“…The working hypothesis of the in vivo and in vitro experiments is presented in Figure 12. Accordingly, TLR-4 is an important pathway for apoptosis and NETosis (36), which could be induced by LPS, DAMPs (from renal-I/R), and DNA histones (from NETosis of PMA and renal-I/R) (100) possibly through the NADPH oxidase 2 (NOX2) dependent pathway (66,102,103). Likewise, Fc gamma receptors are the initiation of NETosis through Syk activation (37).…”

Section: The Increased Susceptibility To Apoptosis and Netosis Of Fcgr2b-/-neutrophils And The Syk Inhibition: A Potential Clinical Transmentioning

confidence: 99%

“…Because of the prominent responses against several stimulators of the Fcgr2b-/-mice (2,7,8), apoptosis and NETosis derived from renal I/R might be more profound than the responses in the normal mice. TLR-4 is the significant pathway that induces both apoptosis and NETosis (36), while spleen tyrosine kinase (Syk) is the shared downstream signaling pathway of TLR-4 and FcgR (20,21,37,38). Therefore, the Syk inhibitor may be an interesting drug to manipulate cell death in renal-I/R mediated cell death in lupus (39).…”

Section: Introductionmentioning

confidence: 99%

Acute Kidney Injury Induced Lupus Exacerbation Through the Enhanced Neutrophil Extracellular Traps (and Apoptosis) in Fcgr2b Deficient Lupus Mice With Renal Ischemia Reperfusion Injury

et al. 2021

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Renal ischemia is the most common cause of acute kidney injury (AKI) that might be exacerbate lupus activity through neutrophil extracellular traps (NETs) and apoptosis. Here, the renal ischemia reperfusion injury (I/R) was performed in Fc gamma receptor 2b deficient (Fcgr2b-/-) lupus mice and the in vitro experiments. At 24 h post-renal I/R injury, NETs in peripheral blood neutrophils and in kidneys were detected using myeloperoxidase (MPO), neutrophil elastase (NE) and citrullinated histone H3 (CitH3), as well as kidney apoptosis (activating caspase-3), which were prominent in Fcgr2b-/- mice more compared to wild-type (WT). After 120 h renal-I/R injury, renal NETs (using MPO and NE) were non-detectable, whereas glomerular immunoglobulin (Ig) deposition and serum anti-dsDNA were increased in Fcgr2b-/- mice. These results imply that renal NETs at 24 h post-renal I/R exacerbated the lupus nephritis at 120 h post-renal I/R injury in Fcgr2b-/- lupus mice. Furthermore, a Syk inhibitor attenuated NETs, that activated by phorbol myristate acetate (PMA; a NETs activator) or lipopolysaccharide (LPS; a potent inflammatory stimulator), more prominently in Fcgr2b-/- neutrophils than the WT cells as determined by dsDNA, PAD4 and MPO. In addition, the inhibitors against Syk and PAD4 attenuated lupus characteristics (serum creatinine, proteinuria, and anti-dsDNA) in Fcgr2b-/- mice at 120 h post-renal I/R injury. In conclusion, renal I/R in Fcgr2b-/- mice induced lupus exacerbation at 120 h post-I/R injury partly because Syk-enhanced renal NETs led to apoptosis-induced anti-dsDNA, which was attenuated by a Syk inhibitor.

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“…Cytokines/Chemokines Another mechanism involved in NET release is autophagy. Several studies have shown that autophagy modifies neutrophil functions [35,36]. Autophagy is a homeostatic mechanism involved in programmed cell death.…”

Section: Microorganismsmentioning

confidence: 99%

The Emerging Role of Neutrophils in the Pathogenesis of Thrombosis in COVID-19

Iliadi

Konstantinidou

Aftzoglou

et al. 2021

IJMS

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Previous studies have shown that COVID-19 leads to thrombotic complications, which have been associated with high morbidity and mortality rates. Neutrophils are the largest population of white blood cells and play a pivotal role in innate immunity. During an infection, neutrophils migrate from circulation to the infection site, contributing to killing pathogens. This mechanism is regulated by chemokines such as IL-8. Moreover, it was shown that neutrophils play an important role in thromboinflammation. Through a diverse repertoire of mechanisms, neutrophils, apart from directly killing pathogens, are able to activate the formation of thrombi. In COVID-19 patients, neutrophil activation promotes neutrophil extracellular trap (NET) formation, platelet aggregation, and cell damage. Furthermore, neutrophils participate in the pathogenesis of endothelitis. Overall, this review summarizes recent progress in research on the pathogenesis of COVID-19, highlighting the role of the prothrombotic action of neutrophils in NET formation.

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TLR4 regulates ROS and autophagy to control neutrophil extracellular traps formation against Streptococcus pneumoniae in acute otitis media

Cited by 23 publications

References 38 publications

Gasdermin D restricts Burkholderia cenocepacia infection in vitro and in vivo

Gasdermin D restricts Burkholderia cenocepacia infection in vitro and in vivo

Acute Kidney Injury Induced Lupus Exacerbation Through the Enhanced Neutrophil Extracellular Traps (and Apoptosis) in Fcgr2b Deficient Lupus Mice With Renal Ischemia Reperfusion Injury

The Emerging Role of Neutrophils in the Pathogenesis of Thrombosis in COVID-19

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