Neutrophil derived microparticles increase mortality and the counter-inflammatory response in a murine model of sepsis

Abstract

Although advances in medical care have significantly improved sepsis survival, sepsis remains the leading cause of death in the ICU. This is likely due to a lack of complete understanding of the pathophysiologic mechanisms that lead to dysfunctional immunity. Neutrophil derived microparticles (NDMPs) have been shown to be the predominant microparticle present at infectious and inflamed foci in human models, however their effect on the immune response to inflammation and infection is sepsis has not been fully elucidated. As NDMPs may be a potential diagnostic and therapeutic target, we sought to determine the impact NDMPs on the immune response to a murine polymicrobial sepsis. We found that peritoneal neutrophil numbers, bacterial loads, and NDMPs were increased in our abdominal sepsis model. When NDMPs were injected into septic mice, we observed increased bacterial load, decreased neutrophil recruitment, increased expression of IL-10 and worsened mortality. Furthermore, the NDMPs express phosphatidylserine and are ingested by F4/80 macrophages via a Tim-4 and MFG-E8 dependent mechanism. Finally, upon treatment, NDMPs decrease macrophage activation, increase IL-10 release and decrease macrophage numbers. Altogether, these data suggest that NDMPs enhance immune dysfunction in sepsis by blunting the function of neutrophils and macrophages, two key cell populations involved in the early immune response to infection.

Bronchoalveolar Lavage Microvesicles Protect Burn-Injured Mice from Pulmonary Infection

“…Microvesicles were isolated as previously described 19 . In brief, bronchoalveolar (BAL) fluid was collected from sham and post burn day 1 (PBD1) mice and centrifuged at 450 × g for 10 minutes at room temperature to form a cell pellet.…”

“…These signals depend largely on the parent cell, which can be lymphocytes, platelets, leukocytes, endothelial and epithelial cells 14,15 . Platelet-derived MVs are the most abundant whereas neutrophil-derived MVs are the dominant type generated at the site of infection 14,19,20 . Neutrophil-derived MVs have been shown to increase the inflammatory response and increase mortality 14,19 .…”

“…Platelet-derived MVs are the most abundant whereas neutrophil-derived MVs are the dominant type generated at the site of infection 14,19,20 . Neutrophil-derived MVs have been shown to increase the inflammatory response and increase mortality 14,19 . While it is known that MVs in bronchoalveolar (BAL) fluid have a role in the immunity of the lung in response to pathogens, the mechanism is unknown 15 .…”

Immune and metabolic alterations following trauma and sepsis – An overview

“…Caldwell and colleagues report that neutrophil derived microparticles can influence the host response in sepsis induced by cecal ligation and puncture (CLP) [7]. The microparticles can modulate target cell function by interaction with cell surface receptors or intra cellular delivery of the cargo containing bioactive factors such as miRNA.…”

“…The microparticles can modulate target cell function by interaction with cell surface receptors or intra cellular delivery of the cargo containing bioactive factors such as miRNA. According to the authors, neutrophil-derived microparticles are the most predominant microparticles observed in sepsis [7] and administration of these microparticles into the mice during CLP increased mortality. The authors conclude that neutrophil-derived microparticles augment immune dysfunction in sepsis by inhibiting innate immune response mediated by neutrophils and macrophages.…”