Pseudomonas quinolone signal induces organelle stress and dysregulates inflammation in human macrophages

Kushwaha, Ankit; Kumar, Virendra; Agarwal, Vishnu

doi:10.1016/j.bbagen.2022.130269

Cited by 10 publications

(7 citation statements)

References 56 publications

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“…As opposed to 2-AA, which dampens the pro-inflammatory response, PQS increases proinflammatory cytokines [55], consistent with the fact that PQS is an acute infection type molecule unrelated to chronic/persistent infections.…”

Section: Discussionsupporting

confidence: 69%

“…Interestingly, the PA QS LasR-regulated homoserine lactone molecule, 3-oxo-C12-HSL, was reported to attenuate the expression of PGC-1α and decreasing the mitochondrial respiratory capacity [27] and promoting apoptosis in lung epithelial cells [54]. Moreover, another PA QS molecule PQS also regulated by LasR was recently shown to induce organelle stress, including mitochondria, by disrupting the mitochondrial membrane potential in human macrophages [55].…”

Section: Discussionmentioning

confidence: 99%

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The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection

Chakraborty,

Bandyopadhaya,

Singh

et al. 2024

Preprint

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How bacterial pathogens exploit host metabolism to promote immune tolerance and persist in infected hosts remains elusive. To achieve this, we show that Pseudomonas aeruginosa (PA), a recalcitrant pathogen, utilizes the quorum sensing (QS) signal 2-aminoacetophenone (2-AA). Here, we unveil how 2-AA-driven immune tolerization causes distinct metabolic perturbations in macrophages mitochondrial respiration and bioenergetics. We found that the 2-AA tolerization impairs oxidative phosphorylation (OXPHOS), leading to decreased generation of the crucial energy metabolite ATP and histone acetylation acetyl-CoA. We provide evidence that these effects result from reduced pyruvate flux into mitochondria due to the decreased expression of the mitochondrial pyruvate carrier (MPC1) mediated via the reduced expression and nuclear presence of its transcriptional regulator estrogen-related nuclear receptor (ERRα), leading to the weaker binding of ERRα to MPC1 promoter. This is the outcome of the hampered interaction of ERRα with the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) that ultimately leads to reduced pyruvate flux into mitochondria and ATP production in tolerized macrophages. Exogenously added ATP in 2-AA exposed macrophages restores the transcript levels of MPC1 and ERR-α and enhances cytokine production and intracellular bacterial clearance. Consistent with the in vitro findings, murine infection studies corroborate the 2-AA-mediated long-lasting decrease in ATP and acetyl-CoA and its association with PA persistence, further supporting this QS signaling molecule as the culprit of the host bioenergetic impairment and PA persistence. These findings unveil 2-AA as a negative modulator of cellular immunometabolism implicating the PGC-1α/ERRα axis in its influence on MPC1/OXPHOS-dependent energy production and PA clearance. These findings shed light on the underlying mechanisms of host tolerance and on potential therapeutic strategies to combat persistent PA infections.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection

Chakraborty,

Bandyopadhaya,

Singh

et al. 2024

Preprint

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“…PQS has been shown to reduce production of IL-12, a proinflammatory cytokine acting as signalling molecules to activate immune cells, leading to pathogen clearance from macrophages, and reduction of Th1 immune response (Skindersoe et al, 2009). PQS can also prompt oxidative stress in macrophages by inducing release of cytosolic Ca 2+ ions, lysosomal instability and endoplasmic reticulum and mitochondrial stress through ROS generation and mitochondrial depolarization (Kushwaha et al, 2023). Hence the presence of PQS interferes with organelle function and cytokine generation, leading to a dysfunction inflammatory response in macrophages.…”

Section: Discussionmentioning

confidence: 99%

Interspecies interactions and biofilm development in a three-species biofilm model

Goh¹

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“…Purified PQS ligand was found to disrupt the MMP and promote mitochondrial ROS in macrophages treated for 6h. These findings were accompanied by dysregulation of inflammatory genes, including downregulation of NLRP3 and IL-1β gene expression and upregulation of Caspase-1, NRLC-4, IL-6, TNF, and IFN-γ genes 234 .…”

Section: Macrophage Response To S Aureus and P Aeruginosamentioning

confidence: 99%

“…Mitochondrial reprogramming governs macrophage function and fine-tunes the macrophage response to environmental stimuli 317 . Several studies have found that stimulation of macrophages with bacterial ligands like LPS is associated with alterations in mitochondrial membrane potential (MMP) and mitochondrial mass that drive mtROS and support NFκB-and inflammasome-mediated inflammatory cytokine production 234,316,318,319 . However, it is unclear how biofilms affect these processes.…”

Section: Sa Is Associated With Heightened Mmp While Pa Induces Loss O...mentioning

confidence: 99%

Unveiling Macrophage-Biofilm Interactions: Implications for Cellular Metabolism and Wound Healing

Versey¹

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Chronic wounds are challenging to treat, cause significant pain, prolong hospitalization, and in the most severe cases, may lead to infection and/or amputations. Understanding the pathophysiology of chronic wounds is crucial for creating novel therapies that promote healing. Bacterial biofilms have been shown to impair wound healing and promote a low-grade inflammatory response. In chronic wounds, macrophages are chronically activated in a pro-inflammatory state and are unable to promote tissue repair. It is unclear what interactions occur between biofilms and macrophages to drive this persistent pro-inflammatory activation. Emerging evidence suggests that mitochondrial reprogramming plays a key role in fine-tuning the macrophage inflammatory response to bacterial infection. In this study, we found that treatment of bone marrow-derived macrophages with conditioned medium containing secreted factors from single-species biofilms of Staphylococcus aureus or Pseudomonas aeruginosa resulted in different patterns of mitochondrial reprogramming and inflammatory responses. S. aureus conditioned media induced a low-grade inflammatory response, associated with a transient reprogramming of the mitochondria to support mitochondrial reactive oxygen species and inflammatory cytokine production. Alternatively, P. aeruginosa conditioned media induced a stronger inflammatory response associated with sustained mitochondrial reprogramming that resulted in prolonged accumulation of mtROS, which eventually resulted in cell death. When macrophages were stimulated with an anti-inflammatory signal, IL-4, they were unable to repolarize to an antiinflammatory state and demonstrated terminal reprogramming towards sustained inflammation.Our findings imply that secreted factors from biofilms (e.g., LPS) may alter mitochondrial function to rewire macrophages to promote prolonged inflammation in chronic wounds. The bacterial species that are present in wounds have a significant impact on this reprogramming. imposter syndrome. When my experiments failed and I began to self-doubt, your patience and constructive feedback helped me continue to progress. You were always positive, motivational, and committed, so I could tackle complicated research problems with the support I needed. You encouraged me to take the initiative to seek solutions and be resilient despite facing setbacks. Not only was I able to work with a fantastic team of people in your lab, but you also fostered collaboration between several research groups that allowed me to target my project from a multidisciplinary approach and conduct high-impact translational research. I am indebted to my co-supervisor and thesis advisory committee members, Dr. Joerg Overhage and Dr. Daniel Pletzer for their infinite guidance and insightful discussions, comments, and expertise throughout my thesis that has helped to improve my scientific approach. I would also like to acknowledge the collaborative efforts of Drs. Katrina DeZeeuw and Jonah Marek.Your expertise greatly helped in the development of th...

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Pseudomonas quinolone signal induces organelle stress and dysregulates inflammation in human macrophages

Cited by 10 publications

References 56 publications

The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection

The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection

Interspecies interactions and biofilm development in a three-species biofilm model

Unveiling Macrophage-Biofilm Interactions: Implications for Cellular Metabolism and Wound Healing

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