Ascorbate and TET2 couple balanced hematopoiesis to disease tolerance

Infections trigger the production of more myeloid cells, but this comes at the expense of reduced blood cell production in other lineages. It is uncertain whether this imbalance is beneficial or harmful, and if factors that encourage balanced hematopoiesis can influence infection outcomes. Researchers have now demonstrated that the ascorbate-TET axis helps maintain a balanced production of blood cells, limits excessive myeloid cell growth, and promotes overall hematopoiesis.

When hematopoietic cells are deprived of ascorbate, it leads to an increase in myeloid cells. This effect is mediated by the activity of TET2 and TET3 enzymes within myeloid progenitor cells. When both ascorbate and TET2 levels are reduced simultaneously, the balance of hematopoiesis is significantly disrupted, favoring the myeloid lineage and hindering erythropoiesis (red blood cell production).

Ascorbate levels are often depleted during infections, but the exact role this depletion plays is not clear. In mice lacking both ascorbate and TET2, infected with the Plasmodium parasite responsible for malaria, the pathogen could still be cleared. However, these mice experienced an overabundance of myeloid cells, a reduced erythroid response, anemia, tissue damage, and ultimately succumbed to the infection, indicating compromised disease tolerance.

The findings suggest that ascorbate and TET2 play a crucial role in maintaining balanced hematopoiesis, which in turn confers tolerance to malaria.