15-Epi-LXA ₄ and 17-epi-RvD1 restore TLR9-mediated impaired neutrophil phagocytosis and accelerate resolution of lung inflammation

Abstract

Timely resolution of bacterial infections critically depends on phagocytosis of invading pathogens by polymorphonuclear neutrophil granulocytes (PMNs), followed by PMN apoptosis and efferocytosis. Here we report that bacterial DNA (CpG DNA) and mitochondrial DNA impair phagocytosis and attenuate phagocytosis-induced apoptosis in human PMNs through Toll-like receptor 9 (TLR9)-mediated release of neutrophil elastase and proteinase 3 and subsequent down-regulation of the complement receptor C5aR. Consistently, CpG DNA delays pulmonary clearance of Escherichia coli in mice and suppresses PMN apoptosis, efferocytosis, and generation of proresolving lipid mediators, thereby prolonging lung inflammation evoked by E. coli. Genetic deletion of TLR9 renders mice unresponsive to CpG DNA. We also show that aspirin-triggered 15-epi-lipoxin A 4 (15-epi-LXA 4 ) and 17-epi-resolvin D1 (17-epi-RvD1) through the receptor ALX/FPR2 antagonize cues from CpG DNA, preserve C5aR expression, restore impaired phagocytosis, and redirect human PMNs to apoptosis. Treatment of mice with 15-epi-LXA 4 or 17-epi-RvD1 at the peak of inflammation accelerates clearance of bacteria, blunts PMN accumulation, and promotes PMN apoptosis and efferocytosis, thereby facilitating resolution of E. coli-evoked lung injury. Collectively, these results uncover a TLR9-mediated endogenous mechanism that impairs PMN phagocytosis and prolongs inflammation, and demonstrate both endogenous and therapeutic potential for 15-epi-LXA 4 and 17-epi-RvD1 to restore impaired bacterial clearance and facilitate resolution of acute lung inflammation. resolution of inflammation | phagocytosis | neutrophils | TLR9 | aspirintriggered LXA 4 and RvD1

The Role of Micronutrients in Support of the Immune Response against Viral Infections

“…These findings supported also by results of animal studies [ 225 , 226 , 227 ], may suggest a potential role for EPA and DHA in reducing the lung injury supporting the resolution of inflammation, probably via the production of SPMs [ 207 ]. However, further trials are needed to support this hypothesis.…”

Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections

“…They found a 19% reduction in individuals taking a daily or weekly dose without bolus doses and no benefit with bolus dosing. Among those receiving a daily or weekly dose, they observed a 25% reduction for those with baseline 25(OH)D levels ≥25 nmol/L (12 ng/mL) and a 70% reduction for those with baseline levels <25 nmol/L [23]. They concluded that daily or weekly vitamin D supplementation protected against ARI overall and that it was safe.…”

“…This could be very important in the context of severe COVID-19 which manifests as uncontrolled inflammation, the so-called cytokine storm [18,19], linked with acute respiratory distress syndrome (ARDS). A number of the SPMs formed from EPA and DHA have been shown in animal models to both protect against and resolve acute lung injury and ARDS [20][21][22][23][24]. Nutritional formulas containing antioxidants and rich in EPA and DHA have been used in several human trials of patients with ARDS.…”

The GPR40 Agonist GW9508 Enhances Neutrophil Function to Aid Bacterial Clearance During E. coli Infections

“…Whilst we found that specific lipid mediators were elevated in response to the GPR40 agonist: these were RvD3, lipoxins, RvE1 and RvE3 ( Figure 4 ). Notably, RvD3, lipoxins and RvE1 are effective in enhancing the clearance of E. coli infection ( 28 ), bacterial pneumonia ( 29 ), and resolution of UV-killed E. coli in human blisters ( 30 ). Systematic analysis of pro-resolving lipid mediator profiles in septic patients with acute respiratory distress syndrome (ARDS) indicated that the amount of circulating 10 S ,17 S -diHDHA (PDX) at day 3 was a better predictor of ARDS development than the APACHE II score ( 31 ), further supporting the role of SPM in regulating host responses during infections.…”