TY - JOUR
T1 - Amphipathic Liponecrosis Impairs Bacterial Clearance and Causes Infection During Sterile Inflammation
AU - Kostenko, Sergiy
AU - Khatua, Biswajit
AU - Trivedi, Shubham
AU - Pillai, Anoop Narayana
AU - McFayden, Bryce
AU - Morsy, Mahmoud
AU - Rajalingamgari, Prasad
AU - Sharma, Vijeta
AU - Noel, Pawan
AU - Patel, Krutika
AU - El-Kurdi, Bara
AU - Borges da Silva, Henrique
AU - Chen, Xianfeng
AU - Chandan, Vishal
AU - Navina, Sarah
AU - Vela, Stacie
AU - Cartin-Ceba, Rodrigo
AU - Snozek, Christine
AU - Singh, Vijay P.
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/10
Y1 - 2023/10
N2 - 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.
AB - 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.
KW - Fatty Acid
KW - Immune Paralysis
KW - Infection
KW - Lipotoxicity
KW - VDAC
UR - http://www.scopus.com/inward/record.url?scp=85169805286&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85169805286&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2023.05.034
DO - 10.1053/j.gastro.2023.05.034
M3 - Article
C2 - 37263302
AN - SCOPUS:85169805286
SN - 0016-5085
VL - 165
SP - 999
EP - 1015
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -