Aspirin-triggered resolvin D1 is produced during self-resolving gram-negative bacterial pneumonia and regulates host immune responses for the resolution of lung inflammation

Abstract

Bacterial pneumonia is a leading cause of morbidity and mortality worldwide. Host responses to contain infection and mitigate pathogen-mediated lung inflammation are critical for pneumonia resolution. Aspirin-triggered resolvin D1 (AT-RvD1; 7S,8R,17R trihydroxy-4Z,9E,11E,13Z,15E,19Z docosahexaenoic acid) is a lipid mediator that displays organ protective actions in sterile lung inflammation, and regulates pathogen-initiated cellular responses. Here, in a self-resolving murine model of Escherichia coli pneumonia, lipid mediator metabololipidomics performed on lungs obtained at baseline, 24 hours and 72 hours after infection uncovered temporal regulation of endogenous AT-RvD1 production. Early treatment with exogenous AT-RvD1 (1 hr post-infection) enhanced clearance of E.coli and Pseudomonas aeruginosa in vivo, and lung macrophage phagocytosis of fluorescent bacterial particles ex vivo. Characterization of macrophage subsets in the alveolar compartment during pneumonia identified efferocytosis by infiltrating macrophages (CD11bHi CD11cLow) and exudative macrophages (CD11bHi CD11cHi). AT-RvD1 increased efferocytosis by these cells ex vivo, and accelerated neutrophil clearance during pneumonia in vivo. These anti-bacterial and pro-resolving actions of AT-RvD1 were additive to antibiotic therapy. Taken together, these findings suggest that the pro-resolving actions of AT-RvD1 during pneumonia represent a novel host-directed therapeutic strategy to complement the current antibiotic centered approach to combatting infections.

Aspirin-triggered resolvin D1 reduces pneumococcal lung infection and inflammation in a viral and bacterial coinfection pneumonia model

“…Importantly, AT-RvD1 significantly reduced NE activity and concurrently restored antimicrobial activity in the BALF of coinfected mice. Our data are consistent with the known actions of AT-RvD1, which can stimulate the production of the antibacterial peptide lipocalin 2, thereby enhancing bacterial clearance in the lung [18].…”

“…Our approach to reduce excessive neutrophil and monocyte inflammation in coinfected mice was to therapeutically deliver exogenous AT-RvD1 during the acute phase of infection. Fpr2 is the main receptor for AT-RvD1 in mice, which reduces neutrophilic inflammation in response to Gram-negative infection [18,19]. Our data demonstrate that AT-RvD1 potently reduces neutrophil and monocyte numbers in the lungs of coinfected mice, thereby significantly limiting the degree of pneumonia.…”

“…Furthermore, exudative macrophages were not reduced by AT-RvD1 in our model. This lung macrophage population is particularly important to resolution processes as RvD1 stimulates exudative macrophages to clear apoptotic neutrophils [18].…”

“…Since mice do not express DRV1/GPR32, Fpr2 represents the major receptor for RvD1 in mice. AT-RvD1 is a promising therapeutic target in bacterial pneumonia as it enhanced macrophage phagocytosis of Gram-negative Escherichia coli and Pseudomonas aeruginosa and accelerated neutrophil efferocytosis during pneumonia to prevent excessive lung injury [18]. AT-RvD1 also promoted more rapid clearance of Gram-negative, non-typeable Haemophilus influenzae by stimulating efferocytosis mediated by M2 skewed macrophages [19].…”

Resolvin D2 decreases TLR4 expression to mediate resolution in human monocytes

“…Resolvin D1 (RvD1) and other SPMs dampen proinflammatory cytokines and cellular influx to reduce LPS-induced tissue destruction and mortality in mice (19,20). SPMs have even been effective against live bacteria, promoting resolution in several models of sepsis and nontypeable Haemophilus influenzae lung infection, restoring lung physiology and reducing the need for antibiotics in infected mice (21)(22)(23). Despite these results showing that SPMs are effective at attenuating bacterial induced, and specifically LPSinduced inflammation, very little is known about the effects of SPMs on TLR expression and signaling, especially in human cells.…”