Lyn prevents aberrant inflammatory responses to Pseudomonas infection in mammalian systems by repressing a SHIP-1-associated signaling cluster

Li, Rongpeng; Fang, Lizhu; Pu, Qinqin; Lin, Ping; Hoggarth, Austin; Huang, Huang; Li, Xuefeng; Li, Guoping; Wu, Min

doi:10.1038/sigtrans.2016.32

Cited by 18 publications

(20 citation statements)

References 58 publications

(93 reference statements)

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“…Functional links between Lyn and STAT3 were also reported previously. Thus, Lyn deletion results in STAT3 activation [ 83 ], and Lyn is required for STAT3 phosphorylation in mast cells [ 84 ]. During B-cell antigen receptor (BCR) engagement, STAT3 was also found to be activated by Lyn, but not by JAK [ 85 ].…”

Section: Discussionmentioning

confidence: 99%

STAT3 Differentially Regulates TLR4-Mediated Inflammatory Responses in Early or Late Phases

Ahuja

Kim

Sung

et al. 2020

IJMS

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Toll-like receptor 4 (TLR4) signaling is an important therapeutic target to manage lipopolysaccharide (LPS)-induced inflammation. The transcription factor signal transducer and activator of transcription 3 (STAT3) has been identified as an important regulator of various immune-related diseases and has generated interest as a therapeutic target. Here, we investigated the time-dependent roles of STAT3 in LPS-stimulated RAW264.7 macrophages. STAT3 inhibition induced expression of the pro-inflammatory genes iNOS and COX-2 at early time points. STAT3 depletion resulted in regulation of nuclear translocation of nuclear factor (NF)-κB subunits p50 and p65 and IκBα/Akt/PI3K signaling. Moreover, we found that one Src family kinase, Lyn kinase, was phosphorylated in STAT3 knockout macrophages. In addition to using pharmacological inhibition of NF-κB, we found out that STAT3KO activation of NF-κB subunit p50 and p65 and expression of iNOS was significantly inhibited; furthermore, Akt tyrosine kinase inhibitors also inhibited iNOS and COX-2 gene expression during early time points of LPS stimulation, demonstrating an NF-κB- Akt-dependent mechanism. On the other hand, iNOS expression was downregulated after prolonged treatment with LPS. Activation of NF-κB signaling was also suppressed, and consequently, nitric oxide (NO) production and cell invasion were repressed. Overall, our data indicate that STAT3 differentially regulates early- and late-phase TLR4-mediated inflammatory responses.

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Section: Discussionmentioning

confidence: 99%

STAT3 Differentially Regulates TLR4-Mediated Inflammatory Responses in Early or Late Phases

Ahuja

Kim

Sung

et al. 2020

IJMS

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“…Immunoblotting also showed decreased cleaved caspase-1 p10 and cleaved IL-1β in Δ oprC -infected cells compared to the PAO1 group, which is consistent with the results from the lungs ( Supplemental Figure 5A ). Furthermore, the STAT3/NF-κB signal pathway in the host has been shown to be activated to promote proinflammatory cytokine expression against P. aeruginosa infection ( 44 , 45 ). The protein levels of STAT3 and NF-κB/p65 in MH-S cells infected with Δ oprC were markedly decreased ( Figure 5A ).…”

Section: Resultsmentioning

confidence: 99%

oprC Impairs Host Defense by Increasing the Quorum-Sensing-Mediated Virulence of Pseudomonas aeruginosa

Gao

Guo

et al. 2020

Front. Immunol.

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Pseudomonas aeruginosa, found widely in the wild, causes infections in the lungs and several other organs in healthy people but more often in immunocompromised individuals. P. aeruginosa infection leads to inflammasome assembly, pyroptosis, and cytokine release in the host. OprC is one of the bacterial porins abundant in the outer membrane vesicles responsible for channel-forming and copper binding. Recent research has revealed that OprC transports copper, an essential trace element involved in various physiological processes, into bacteria during copper deficiency. Here, we found that oprC deletion severely impaired bacterial motility and quorum-sensing systems, as well as lowered levels of lipopolysaccharide and pyocyanin in P. aeruginosa. In addition, oprC deficiency impeded the stimulation of TLR2 and TLR4 and inflammasome activation, resulting in decreases in proinflammatory cytokines and improved disease phenotypes, such as attenuated bacterial loads, lowered lung barrier damage, and longer mouse survival. Moreover, oprC deficiency significantly alleviated pyroptosis in macrophages. Mechanistically, oprC gene may impact quorum-sensing systems in P. aeruginosa to alter pyroptosis and inflammatory responses in cells and mice through the STAT3/NF-κB signaling pathway. Our findings characterize OprC as a critical virulence regulator, providing the groundwork for further dissection of the pathogenic mechanism of OprC as a potential therapeutic target of P. aeruginosa.

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“…Lung tissues were fixed in 10% formalin (Sigma-Aldrich) for 72 h and then were infiltrated in 20% sucrose for 72 h. Tissues were embedded in OCT (optimal cutting temperature compound), cut by cryostat and stained by standard H&E protocol. 46 The slides were imaged by Nikon Eclipse 80i microscopy by 20× objective.…”

Section: Methodsmentioning

confidence: 99%

Bitter receptor TAS2R138 facilitates lipid droplet degradation in neutrophils during Pseudomonas aeruginosa infection

Guo

Lin

et al. 2021

Sig Transduct Target Ther

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Bitter receptors function primarily in sensing taste, but may also have other functions, such as detecting pathogenic organisms due to their agile response to foreign objects. The mouse taste receptor type-2 member 138 (TAS2R138) is a member of the G-protein-coupled bitter receptor family, which is not only found in the tongue and nasal cavity, but also widely distributed in other organs, such as the respiratory tract, gut, and lungs. Despite its diverse functions, the role of TAS2R138 in host defense against bacterial infection is largely unknown. Here, we show that TAS2R138 facilitates the degradation of lipid droplets (LDs) in neutrophils during Pseudomonas aeruginosa infection through competitive binding with PPARG (peroxisome proliferator-activated receptor gamma) antagonist: N-(3-oxododecanoyl)-l-homoserine lactone (AHL-12), which coincidently is a virulence-bound signal produced by this bacterium (P. aeruginosa). The released PPARG then migrates from nuclei to the cytoplasm to accelerate the degradation of LDs by binding PLIN2 (perilipin-2). Subsequently, the TAS2R138–AHL-12 complex targets LDs to augment their degradation, and thereby facilitating the clearance of AHL-12 in neutrophils to maintain homeostasis in the local environment. These findings reveal a crucial role for TAS2R138 in neutrophil-mediated host immunity against P. aeruginosa infection.

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Lyn prevents aberrant inflammatory responses to Pseudomonas infection in mammalian systems by repressing a SHIP-1-associated signaling cluster

Cited by 18 publications

References 58 publications

STAT3 Differentially Regulates TLR4-Mediated Inflammatory Responses in Early or Late Phases

STAT3 Differentially Regulates TLR4-Mediated Inflammatory Responses in Early or Late Phases

oprC Impairs Host Defense by Increasing the Quorum-Sensing-Mediated Virulence of Pseudomonas aeruginosa

Bitter receptor TAS2R138 facilitates lipid droplet degradation in neutrophils during Pseudomonas aeruginosa infection

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