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The study, published in Nature, describes a complete pathway from parasite infection through to the chromatin-level changes that allow the organism to respond to it.
In collaboration with groups at the Kennedy Institute in Oxford, the Francis Crick Institute in London, the University of Sussex and Trinity College Dublin, researchers at the MRC Weatherall Institute of Molecular Medicine identified the molecular mechanisms that increase production of basophils, eosinophils and mast cells. These are myeloid cell types essential for the type 2 immune response against worms and other parasites. However, overproduction of these cells can cause allergic inflammation, asthma and mast cell disorders. So, this paper’s findings also revealed a potential drug target for treating these diseases.
Two pathways for innate immune cells
Myeloid cells are part of the innate immune system, which provides rapid, first-line defence against bacteria, viruses and parasites. For a long time, scientists believed all myeloid cells arose from a single common progenitor. However, previous work from the Nerlov Group demonstrated that there are in fact two distinct developmental routes: one that generates neutrophils and macrophages (mainly involved in the type 1 immune response against bacteria and viruses), and another that produces basophils, eosinophils and mast cells (critical for the type 2 immune response against parasite infection).
While the bacterial-response pathway has been extensively studied, far less was known about how the parasite-response pathway is regulated.
“This raised a fundamental question,”
said Dr Alexandre Fagnan, a European Haematology Association Junior Research Grant recipient who is the first author of the study.
If there are two separate production lines for myeloid cells, how does the body control them independently, depending on the type of infection?
From infection to gene control
The team used a mouse model of helminth (parasitic worm) infection to show that infection increases the level of immune signalling molecule IL-33 in the bone marrow. IL-33 is known as an “alarmin”—a molecule released by damaged tissues that alerts the immune system.
They showed that IL-33 acts directly on early blood progenitor cells, triggering them to increase production of a protein called LMO4. Although LMO4 does not bind DNA itself, it partners with GATA-2, a master regulator of blood cell development.
Normally, GATA-2 helps control the balance between making red blood cells, platelets and type 2 myeloid cells. The researchers discovered that LMO4 changes how GATA-2 works: it redirects GATA-2 away from genes involved in red blood cell and platelet production toward genes that drive the formation of basophils, eosinophils and mast cells – key cell types in parasite defence.
In effect, infection activates a molecular switch that reallocates GATA-2 across the genome, reprogramming blood cell development to meet the immune challenge.
To confirm this mechanism, the researchers studied mice carrying a mutation in GATA-2 that prevents it from interacting with LMO4. In these mice, the switch could not be flipped. The mice produced fewer parasite-fighting cells and were less able to control parasite infection.
The team also showed that the same IL-33–LMO4 pathway operates in human blood progenitor cells, suggesting this infection-driven genetic switch is a conserved feature of immune regulation.
Speaking about the study, senior author Professor Claus Nerlov said:
Overall, this provides a detailed view of how parasite infection increases the production of the cells that fight the parasite at both the cellular and molecular level. What I really like about the paper is that it manages to generate a complete pathway from the parasite infection all the way to the chromatin-level changes that allow the organism to respond to it (and show that these are physiologically important).
Another aspect is that LMO4 (and the LMO4–GATA-2 interaction in particular) is a new drug target for diseases where type 2 myeloid cells are pathological (mastocytosis, eosinophilic asthma) - in fact, we are already working on making small molecules that can degrade LMO4 or block its activity.
Read the full paper in Nature: A mechanism to initiate emergency type 2 myelopoiesis.