Harvard Catalyst Profiles

I am passionate about understanding how neutrophils contribute to health and disease. Neutrophils are the largest white blood cell population in the blood (in humans, 60% of white blood cells are neutrophils). Neutrophils are mentioned daily by physicians and the neutrophil absolute count is one of the most common blood tests prescribed for evaluating patient defenses against microbes. However, new discoveries are changing the paradigm of neutrophil functions. Enabled by novel technologies to study neutrophils ex vivo, new assays are emerging to study the contribution of human neutrophils to the pathology of numerous diseases:

(1) The traffic of neutrophils is traditionally considered to be unidirectional, from the blood to the tissue, guided by chemoattractant gradients (after which neutrophils die and are removed by macrophages). Using inflammation-on-a-chip devices, we showed for the first time that human neutrophils continue migrating persistently after reaching the highest chemoattractant concentration and all (100%) can be directed back to the starting location. Reports in zebrafish and mice confirmed that neutrophils are capable of reversing migration from tissues to circulation. These findings establish the fundamental basis for testing the functionality of neutrophils in blood and designing novel assays to diagnose and monitor inflammations, infections, and sepsis.

(2) Neutrophils often interact with common pathogens that are larger than what one neutrophil could phagocytose (e.g. clusters of bacteria – S.aureus or S.pyogenes, elongated hyphae of filamentous fungi – Candida and Aspergillus). During these interactions, a novel behavior can be observed, where neutrophils cooperate against targets (a process named swarming). We designed the first high-throughput platform for the systematic study of human neutrophil swarming ex vivo (Reategui et al, Nat Bio Eng, 2016). We leveraged this platform to uncover a complex constellation of mediators that coordinate the activity of multiple neutrophils against large targets and mediate their interactions with leukocytes and non-immune cells, effectively placing the neutrophils at the center of immune responses.

(3) Neutrophils can release chromatin to trap microbes (neutrophil extracellular traps - NETs). Originally, NETs were proposed to play antimicrobial functions. This paradigm is shifting, following the discovery of biochemical properties responsible for complications in autoimmune diseases, diabetes, and cancer. Our contribution to this paradigm shift is the design of devices to test the mechanical role for the chromatin fibers encompassing the NETs, during inflammation and sepsis (Boneshaker et al, Int. Bio, 2016). Our findings challenge the traditional view of capillary plexuses providing robust delivery of oxygen to tissues. On the contrary, we determined that capillary plexuses are vulnerable to neutrophils and NETs, which can completely disrupt their normal function, triggering hypoxia and leading to organ failure during infections and sepsis.
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