Resolvin D1 Dampens Pulmonary Inflammation and Promotes Clearance of Nontypeable Haemophilus influenzae

Abstract

Nontypeable Haemophilus influenzae (NTHi) is a gram-negative, opportunistic pathogen that frequently causes ear infections, bronchitis, pneumonia, and exacerbations in patients with underlying inflammatory diseases, such as chronic obstructive pulmonary disease. In mice, NTHi is rapidly cleared, but a strong inflammatory response persists, underscoring the concept that NTHi induces dysregulation of normal inflammatory responses and causes a failure to resolve. Lipid-derived specialized pro-resolving mediators (SPMs) play a critical role in the active resolution of inflammation by both suppressing pro-inflammatory actions and promoting resolution pathways. Importantly, SPMs lack the immune suppressive properties of classical anti-inflammatory therapies. Based on these characteristics, we hypothesized that aspirin-triggered resolvin D1 (AT-RvD1) would dampen NTHi-induced inflammation while still enhancing bacterial clearance. C57BL/6 mice were treated with AT-RvD1 and infected with live NTHi. AT-RvD1 treated mice had lower total cell counts and neutrophils in bronchoalveolar lavage fluid (BALF), and had earlier influx of macrophages. Additionally, AT-RvD1 treated mice showed changes in temporal regulation of inflammatory cytokines and enzymes, with decreased KC at 6hrs and decreased IL-6, TNFα, and Cox-2 expression at 24hrs post-infection. Despite reduced inflammation, AT-RvD1 treated mice had reduced NTHi bacterial load, mediated by enhanced clearance by macrophages and a skewing towards an M2 phenotype. Finally, AT-RvD1 protected NTHi-infected mice from weight loss, hypothermia, hypoxemia and respiratory compromise. This research highlights the beneficial role of SPMs in pulmonary bacterial infections, and provides the groundwork for further investigation into SPMs as alternatives to immunosuppressive therapies like steroids.

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

“…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.…”

“…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]. Here, we demonstrate that in our bacterial and viral coinfection model associated with increased neutrophilic inflammation, levels of circulating and lung tissue SAA remained markedly elevated during the resolution phase following pneumococcal infection (7 days post-SP inoculation).…”

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.…”

The persistence of Nontypeable Haemophilus influenzae fuels airway inflammation

“…Airway persistence of NTHi is common in CF disease but also in other lung diseases with different aetiology, including COPD or lung cancer [29][30][31]. In this context, Croasdell A. et al exploited an acute infection model in which different amounts of NTHi were inoculated by oropharyngeal aspiration in C57BL/6J mice (up to 10 8 CFU) and 24 hours post-infection they found >90% of bacteria had been cleared, independently from the inoculum dose [32]. To date, mouse models based on the injection of NTHi planktonic bacterial cells in immunocompetent mice are useful for studying the acute infection phase rather than NTHi persistence.…”