New study sheds light on when and how neutrophils arm their microbe-killing proteins

The first line of defense in our immune systems comprises white blood cells, with neutrophils making up 40% to 70% of them. Neutrophils rush to sites of injury or infection, releasing proteins that promote inflammation and combat invading microbes. During this response, these proteins are adorned with carbohydrate molecules known as glycoproteins. However, the exact timing and process of glycosylation in neutrophils have remained a mystery.

Now, an international research team may be one step closer to unraveling this mystery, potentially refining personalized immune responses. Their findings were published in the Proceedings of the National Academy of Sciences.

Morten Thaysen-Andersen, the corresponding author and an Associate Professor at Macquarie University in Australia, explained, “We know that the microbicidal proteins produced by neutrophils are modified by functionally relevant complex carbohydrates called glycans, but we still don’t understand the specifics of when and how this glycosylation occurs. This knowledge is crucial for understanding innate immune processes, including pathogen defense.”

Neutrophils exist in the blood in a resting state, equipped with subcellular compartments containing antimicrobial glycoproteins. These compartments are mobilized when specific environmental cues trigger neutrophils to move to infection sites and respond appropriately.

To shed light on this process, the researchers isolated neutrophils from blood donors, extracted the intracellular cytosolic granules, and analyzed the glycan-decorated proteins within them. By examining four types of intracellular organelles in neutrophils throughout their maturation stages, they mapped how and when glycosylation occurred in neutrophil proteins involved in microbial defense and inflammation.

Thaysen-Andersen highlighted their discovery that neutrophil-produced microbicidal proteins are heavily decorated with unique glycans, and these unusual glycosylation patterns are specific to particular compartments within the neutrophils.

Their analysis revealed that the coordinated expression of a specific glycoprotein early in neutrophil maturation was responsible for this restricted subcellular origin. This glycoprotein expression coincided with the initial development of the organelle responsible for the microbicidal response.

This finding, according to Thaysen-Andersen, offers a valuable resource for future studies on neutrophil glycosylation’s biological roles and potential dysregulation. He emphasized that this precise map of healthy neutrophils could be used to investigate glycosylation in immature neutrophils during emergency granulopoiesis (the generation of new neutrophils in response to acute infection or septic shock) and in patients with acute myeloid leukemia. These efforts could reveal new insights into glycoprotein-related immune responses in both normal and abnormal physiological conditions.

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