Cystatin C regulates the cytotoxicity of infection‐induced endothelial‐derived β‐amyloid

Balczon, Ron; Morrow, K. Adam; Leavesley, Silas J.; Francis, C.M.; Stevens, T.; Agwaramgbo, Ezinne; Williams, Christopher; Stevens, R.P.; Langham, Geri; Voth, S.B.; Cioffi, Eugene A.; Weintraub, Susan E; Stevens, Troy

doi:10.1002/2211-5463.12997

Cited by 4 publications

(4 citation statements)

References 54 publications

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“…We have previously shown that Gram-positive and Gram-negative organisms that cause pneumonia trigger the release of cytotoxic tau variants from lung endothelium, as quantified using Western blotting with antibodies selective for various tau species (e.g., TOC1, TauC3, Tau5, and T22) (17,31). In a recent study, we determined the 'bioactivity' of endothelium-derived tau and amyloid species released from lung endothelium after infection with P. aeruginosa strain variants (32).…”

Section: Resultsmentioning

confidence: 99%

Cytotoxic tau released from lung microvascular endothelial cells upon infection with Pseudomonas aeruginosa promotes neuronal tauopathy

Gwin

Voth

et al. 2022

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

Cytotoxic tau released from lung microvascular endothelial cells upon infection with Pseudomonas aeruginosa promotes neuronal tauopathy

Gwin

Voth

et al. 2022

Journal of Biological Chemistry

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“…Lung endothelium produces Aβ ( 15 , 17 , 23 ). Amyloid concentrations are increased in the bronchoalveolar lavage fluid and plasma of patients with pneumonia ( 18 , 39 ), and here, we observed increased Aβ 42 in the circulation of wild-type rats and increased Aβ 42/40 ratios in both wild-type and GSAP KO rats postinfection.…”

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, the increase in circulating amyloids during infection cannot be specifically attributed to their production by lung endothelium. As Aβ 40 and Aβ 42 can be cytotoxic to the host ( 23 ), these infection-elicited amyloids may be an independent cause of injury to the alveolar-capillary barrier. Amyloids can also have antimicrobial properties ( 11 – 15 ).…”

Section: Discussionmentioning

confidence: 99%

“…Aβ is increased in the bronchoalveolar lavage fluid, blood, and/or cerebrospinal fluid during infection ( 16 – 18 ), and infection is potentially an adverse effect of Aβ-lowering medical therapy ( 19 ). Aβ contributes to the pathogenesis of ischemic heart disease ( 20 ), it can activate platelets ( 21 ), and it can injure the lung ( 22 , 23 ). Although these studies suggest a central role for Aβ in the innate immune response, mechanisms contributing to the increase in Aβ during infection are unresolved.…”

Section: Introductionmentioning

confidence: 99%

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Gamma secretase activating protein promotes end-organ dysfunction after bacterial pneumonia

Gwin

Alexeyev

Geurts

et al. 2023

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pneumonia elicits the production of cytotoxic beta amyloid (Ab) that contributes to end-organ dysfunction, yet the mechanism(s) linking infection to activation of the amyloidogenic pathway that produces cytotoxic Ab is unknown. Here, we tested the hypothesis that g-secretase activating protein (GSAP), which contributes to the amyloidogenic pathway in the brain, promotes end-organ dysfunction following bacterial pneumonia. First-in-kind GSAP knockout rats were generated. Wild type and knockout rats possessed similar body weights, organ weights, circulating blood cell counts, arterial blood gases, and cardiac indices at baseline. Intratracheal Pseudomonas aeruginosa infection caused acute lung injury and a hyperdynamic circulatory state. Whereas infection led to arterial hypoxemia in wild type rats, the alveolar-capillary barrier integrity was preserved in GSAP knockout rats. Infection potentiated myocardial infarction following ischemia-reperfusion injury, and this potentiation was abolished in knockout rats. In the hippocampus, GSAP contributed to both pre- and postsynaptic neurotransmission, increasing the presynaptic action potential recruitment, decreasing neurotransmitter release probability, decreasing the postsynaptic response, and preventing postsynaptic hyperexcitability, resulting in greater early long-term potentiation but reduced late long-term potentiation. Infection abolished early and late long-term potentiation in wild type rats, whereas the late long-term potentiation was partially preserved in GSAP knockout rats. Furthermore, hippocampi from knockout rats, and both the wild type and knockout rats following infection, exhibited a GSAP-dependent increase in neurotransmitter release probability and postsynaptic hyperexcitability. These results elucidate an unappreciated role for GSAP in innate immunity and highlight the contribution of GSAP to end-organ dysfunction during infection.

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Pseudomonas aeruginosa ExoY infection of pulmonary microvascular endothelial cells releases cyclic nucleotides into the extracellular compartment

Stone,

Choi,

Dey

et al. 2024

American Journal of Physiology-Lung Cellular and Molecular Phys

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Type three secretion system (TTSS) competent Pseudomonas aeruginosa expressing soluble promiscuous cyclase, ExoY, generates cyclic nucleotides in pulmonary microvascular endothelial cells (PMVECs). Within cells, cyclic nucleotide signals are highly compartmentalized, but these second messengers are also released into the extracellular space. While agonist-stimulation of endogenous adenylyl cyclase (AC) or the presence of ExoY increases cyclic nucleotides, the proportion of the signal that is in the intracellular versus extracellular compartments is unresolved. Further, it is unclear whether P. aeruginosa primary infection or treatment with sterile media supernatants derived from a primary infection, alters beta-adrenergic agonist-induced elevations in cAMP in PMVECs. Herein, we determine that PMVECs release cAMP into the extracellular space constitutively, following beta-adrenergic stimulation of endogenous AC, and following infection with P. aeruginosa expressing ExoY. Surprisingly, in PMVECs, only a small proportion of cGMP is detected within the cell at baseline or following P. aeruginosa ExoY-infection with a larger proportion of total cGMP being detected extracellularly. Thus, the ability of lung endothelium to generate cyclic nucleotides may be underestimated by examining intracellular cyclic nucleotides alone, since a large portion is delivered into the extracellular compartment. In addition, P. aeruginosa infection or treatment with sterile media supernatants from a primary infection suppress the beta-adrenergic cAMP response, which is further attenuated by the expression of functional ExoY. These findings reveal an overabundance of extracellular cyclic nucleotides following infection with ExoY expressing TTSS competent P. aeruginosa.

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Cystatin C regulates the cytotoxicity of infection‐induced endothelial‐derived β‐amyloid

Cited by 4 publications

References 54 publications

Cytotoxic tau released from lung microvascular endothelial cells upon infection with Pseudomonas aeruginosa promotes neuronal tauopathy

Cytotoxic tau released from lung microvascular endothelial cells upon infection with Pseudomonas aeruginosa promotes neuronal tauopathy

Gamma secretase activating protein promotes end-organ dysfunction after bacterial pneumonia

Pseudomonas aeruginosa ExoY infection of pulmonary microvascular endothelial cells releases cyclic nucleotides into the extracellular compartment

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