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With 350,000 new patients diagnosed each year worldwide, sickle cell disease is considered the most common genetic disease. It is caused by a mutation leading to a structural defect in hemoglobin, the main component of red blood cells. The main symptoms of this disease are: anemia, painful "vaso-occlusive" attacks, but also chronic inflammation leading, in the long term, to insufficiencies in various organs: liver, kidneys, heart, etc.
Scientists have known for a long time that this inflammation (more or less severe depending on the patient) is due to an abnormal activation of a family of immune cells called monocytes. But the exact mechanism of this activation was not yet known. In a new study published in the journal Blood, researchers from the laboratory "Cellular and molecular mechanisms of hematological disorders and therapeutic implications" at Institut Imagine (Inserm, AP-HP, Université Paris Cité), report for the first time the discovery of the molecular basis of this activation [1].
It starts with the process of hemolysis that occurs chronically in sickle cell disease and during which red blood cells are destroyed, releasing different molecules into the bloodstream, in particular sickle hemoglobin (HbS) and heme, an iron compound present in hemoglobin. "The scientific community suspected a key role for heme in inflammation, but this hypothesis had yet to be verified," says Thiago Trovati, Inserm research fellow, theme leader at Institut Imagine and coauthor of the publication.
The key role of circulating sickle hemoglobin
To explore this hypothesis, the researchers analyzed the inflammatory response in another red blood cell disease: beta thalassemia. Unlike sickle cell disease, in beta thalassemia, hemoglobin is healthy but is produced in insufficient quantities, leading to severe anemia in patients. "As in sickle cell disease, we observed that free heme increases in beta thalassemia. However, this increase is not accompanied by inflammatory activation. In other words, heme alone cannot explain inflammation. "By studying different models we have been able to show that the inflammation observed in sickle cell disease is triggered not by the presence of heme but by the presence of the diseased hemoglobin circulating freely in the blood," says Thiago Trovati.
Morever, scientists were able to show that the diseased hemoglobin (HbS) is able to bind to TLR4 receptors on monocytes, triggering inflammation. "This discovery is important because it points to a new therapeutic target. Indeed, if we find molecules capable of inhibiting the activation of the TLR4 receptor, we could stop this inflammatory process," says the researcher.
Inflammation is not sufficiently taken into account
"Inflammation is truly a major component of sickle cell disease that is currently not sufficiently taken into account in the various therapeutic strategies. It has been shown that this inflammation is strongly correlated with mortality in sickle cell patients and it is urgent to understand its origin in order to consider new treatments for the disease," concludes Slimane Allali, first author of the publication and a pediatrician at the Sickle Cell Center of the Hôpital Necker-Enfants malades (AP-HP, Université Paris Cité).
[1] S. Allali et al, Blood, doi.org/10.1182/blood.2021014894, 2022