How do respiratory allergic reactions occur? Westlake University has made a new discovery

In the cool autumn weather, a tiny grain of pollen can easily cause an allergic reaction in the human body. What exactly is an allergy? What is going on in the body's immune system when an allergic reaction occurs?

In fact, the process of allergy is much more complicated than what we perceive. Recently, the research group of Xu Heping from Westlake University and Westlake Laboratory published a research result entitled "Alarmin-loaded extracellular lipid droplets induce airway neutrophil infiltration during type 2 inflammation" in the journal Immunity. The study showed that lipid droplets released by type 2 innate lymphoid cells (ILC2) can activate and recruit neutrophils, thereby promoting allergic inflammatory responses in the airways.

This discovery expands the understanding of the interaction between type 2 innate lymphoid cells (ILC2) and neutrophils, proposes a new immune communication pathway independent of the traditional type 2 cytokine-mediated downstream effector cell recruitment mechanism, and reveals lipid droplets as a new carrier of information transmission between immune cells, providing a new perspective for understanding the potential mechanism of abnormal accumulation of neutrophils in allergic diseases such as severe asthma.

This research project of Xu Heping's research group is centered around the mechanism of type 2 inflammatory response. In previous studies, type 2 inflammatory response is an important defense mechanism for the body against large pathogens such as invading parasites and allergens, and is also a key factor in maintaining the physiological balance of various systems in the body. However, overactive type 2 inflammatory response can lead to chronic diseases such as allergies. These chronic inflammatory diseases currently lack effective cures in clinical practice, which seriously affects the quality of life of patients and imposes a burden on the social economy.

The core hallmark of type 2 inflammatory response is the production of type 2 inflammatory cytokines such as interleukin (IL)-4, IL-5 and IL-13. Type 2 innate lymphoid cells are the key regulators of type 2 inflammatory response. By secreting a large amount of type 2 inflammatory cytokines, activated type 2 innate lymphoid cells can activate downstream effector cells, thereby promoting the progress of type 2 inflammatory response. It can be said that type 2 innate lymphoid cells are one of the important "switches" of type 2 inflammatory response.

Clinical data also show that the number of neutrophils in the airways of patients with severe asthma also increases significantly. Xu Heping's research group used different immune cell-deficient mice to construct an asthma model. Two sets of experiments proved that there is a correlation between ILC2 and neutrophils, and that ILC2 can recruit neutrophils to infiltrate the respiratory tract to participate in allergic inflammatory responses.

The complete chain of respiratory allergies is gradually becoming clear. First, allergens such as viruses, dust mites, and pathogens enter the body through the respiratory tract. After the respiratory tract comes into contact with these allergens, the inflammatory cytokine IL-33, which mainly exists in epithelial cells, receives these allergic signals and then activates type 2 innate lymphoid cells. The activated ILC2 will secrete HMGB1, informing and recruiting neutrophils.

After that, the research team discovered and proved through a series of experiments that "lipid droplets" are the main storage place for neutral lipids in cells. In addition to storing energy, they also play an important role in membrane transport, protein degradation, and signal transduction.

Lipid droplets are small balls containing fat, wrapped by a layer of membrane. When inflammation occurs, the lipid droplets will be released outside the cell. Groups of key protein molecules will "hitch a ride" on the lipid droplets and attach to the membrane proteins of the lipid droplets, like putting a "wreath" on the lipid droplets. When they arrive outside the cell, some HMBG1 will get off halfway, while others will reach the end, telling the neutrophils that inflammation is occurring in the respiratory tract and requesting support.

The research results previously published by Xu Heping's research group revealed that intracellular lipid droplets can serve as energy reserves to support the rapid proliferation of ILC2, thereby promoting type 2 inflammatory response (Zang et al, Immunity 2023). The new results this time found that ILC2 can release lipid droplets carrying HMGB1 alarmin molecules into the extracellular environment. These extracellular lipid droplets can effectively activate and recruit neutrophils to infiltrate the respiratory tract, thereby aggravating allergic inflammatory responses.