The Role of Emergency Neutrophils and Glycans in Postoperative and Septic Patients

Postoperative complications of any sort occurs in many of the patients undergoing high risk cancer surgery such as surgery for pancreatic, esophageal or ovarian malignancy (3, 4) These patients have a risk of wound infection mainly due to malnutrition and challenging surgical conditions (5, 6) A prolonged inflammatory response (overshoot) in some patients may lead to multiple organ failure (MOF) (7, 8).

Postoperative immunosuppression However, to handle the postoperative proinflammatory actions, patients also produce anti-inflammatory cytokines, mainly IL-4, IL-10 and IL-1 Ra. This is called compensatory inflammatory response syndrome (CARS). In cases of complications or malnutrition there may instead be an overshoot of the CARS mechanisms that lead to a suppression of the immune response (9, 10).

The surgical stress resulting in an imbalance in the inflammatory systems consume the circulating neutrophils and stresses the bone marrow to release immature, less efficient neutrophils, into the bloodstream, an event called emergency granulopoesis(11, 12).

Sepsis and ARDS Sepsis is one of the leading causes of death in Sweden and globally, and is characterized by an uncontrolled inflammatory reaction (13). The disease can affect everyone, including previously healthy people, and occurs when a normal bacterial infection invades the bloodstream and the body then responds with an inflammatory reaction. Acute organ dysfunction in sepsis primarily affects respiratory and circulatory systems (14). Pneumonia is the most common underlying cause of sepsis and respiratory insufficiency is the most common organ dysfunction in septic shock (15). Pneumonia with septic shock can develop into respiratory distress syndrome (ARDS) associated with a very high mortality rate, around 40% (16-18) Recently, ARDS was shown to be associated with migration of neutrophils, into the lung alveoli, and that such infiltration drives an inflammatory reaction, for which the pathophysiological mechanisms are incompletely mapped. Increased knowledge of the neutrophil role in ARDS could thus benefit the understanding of this complex syndrome(19, 20). In sepsis, the demand for enough circulating neutrophils to fight the infection is so high that reserve pools are exhausted and granulopoiesis switches to emergency mode. This results in release of immature neutrophils into circulation, the so-called left shift, used as an indicator of sepsis. As a result, circulating neutrophils in sepsis can be very heterogeneous, an effect also seen in autoimmune diseases and cancer (21). There are currently no tools to properly investigate these emergency neutrophil populations to utilize for diagnosis and disease follow-up.

Neutrophils and emergency granulopoesis Polymorphonuclear neutrophils constitute the most abundant population of white blood cells. Their main task is to provide innate immune protection of the host from microbial attack, migrating to the site of infection, engulfing the microbes by phagocytosis, and killing the prey through attack by reactive oxygen species (ROS) and antimicrobial granule pro¬teins (22). Upon systemic infection or inflammation, e.g., sepsis or trauma, the bone marrow enters a state of emergency granulopoiesis, drenched in cytokines that augment production and survival of neutrophils for rapid delivery to the blood (23-25). Recently, advanced techniques have evolved that al¬low the isolation of different developmental stages of steady-state and emergency neutrophils, and characterization of these has just begun (26). Glycans Glycans (polysaccharides) attached to proteins and lipids on the surfaces on immune cells serve as ligands for glycan-binding proteins, lectins. Several neutrophil processes are directed by gly¬can - lectin interactions; selectin-directed rolling on the endothelium, siglec-mediated in¬hibitory signals, and activation of effector function by galectins. Many of the proteins that end up in neutrophil intra-cellular granules are highly glycosylated, but not much is known about if and how the neutrophil glycome evolves during the 'targeting-by-timing' process of differentiation and how this is affected by emergency granulopoiesis during systemic infection and inflammation. Here is a clear knowledge gap.