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Published on: March 29, 2017
Amphipathic Liponecrosis Impairs Bacterial Clearance and Causes Infection During Sterile Inflammation
Sergiy Kostenko1, Biswajit Khatua1, Shubham Trivedi1
1Department of Medicine, Mayo Clinic, Rochester, Minnesota.
Background & Aims:
Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have grave consequences. We examined how impaired bacterial clearance may cause this transition.
Methods:
Blood samples from patients with AP, normal controls, and rodents with pancreatitis or those administered different nonesterified fatty acids (NEFAs) were analyzed for albumin-unbound NEFAs, microbiome, and inflammatory cell injury. Macrophage uptake of unbound NEFAs using a novel coumarin tracer were done and the downstream effects-NEFA-membrane phospholipid (phosphatidylcholine) interactions-were studied on isothermal titration calorimetry.
Results:
Patients with infected AP had higher circulating unsaturated NEFAs; unbound NEFAs, including linoleic acid (LA) and oleic acid (OA); higher bacterial 16S DNA; mitochondrial DNA; altered β-diversity; enrichment in Pseudomonadales; and increased annexin V-positive myeloid (CD14) and CD3-positive T cells on admission. These, and increased circulating dead inflammatory cells, were also noted in rodents with unbound, unsaturated NEFAs. Isothermal titration calorimetry showed progressively stronger unbound LA interactions with aqueous media, phosphatidylcholine, cardiolipin, and albumin. Unbound NEFAs were taken into protein-free membranes, cells, and mitochondria, inducing voltage-dependent anion channel oligomerization, reducing ATP, and impairing phagocytosis. These were reversed by albumin. In vivo, unbound LA and OA increased bacterial loads and impaired phagocytosis, causing infection. LA and OA were more potent for these amphipathic interactions than the hydrophobic palmitic acid.
Conclusions:
Release of stored LA and OA can increase their circulating unbound levels and cause amphipathic liponecrosis of immune cells via uptake by membrane phospholipids. This impairs bacterial clearance and causes infection during sterile inflammation.
Insights
Infections during sterile diseases like acute pancreatitis (AP) can arise from impaired bacterial clearance. Elevated unbound fatty acids disrupt immune cell function, leading to bacterial overgrowth and infection during sterile inflammation.
Area of Science:
- Microbiology
- Immunology
- Biochemistry
Background:
- Transient bacteremia is common after procedures, but infections during sterile diseases like acute pancreatitis (AP) are severe.
- The mechanisms linking sterile inflammation to bacterial infection remain unclear.
Purpose of the Study:
- To investigate how impaired bacterial clearance contributes to infections in acute pancreatitis.
- To examine the role of nonesterified fatty acids (NEFAs) in this process.
Main Methods:
- Analyzed blood samples from AP patients and rodents for NEFAs, microbiome, and inflammatory markers.
- Studied macrophage uptake of NEFAs and their interactions with phospholipids using calorimetry.
- Assessed the impact of NEFAs on immune cell function and bacterial loads in vivo.
Main Results:
- Infected AP patients and rodents showed higher levels of unsaturated, unbound NEFAs (linoleic and oleic acids).
- Unbound NEFAs impaired immune cell phagocytosis and mitochondrial function, increasing bacterial loads.
- Albumin reversed these detrimental effects, while hydrophobic fatty acids were less potent.
Conclusions:
- Elevated circulating unbound NEFAs can cause liponecrosis of immune cells during sterile inflammation.
- This impairs bacterial clearance, leading to infection in conditions like acute pancreatitis.
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