Research ArticleInflammation

Inflammation induces stress erythropoiesis through heme-dependent activation of SPI-C

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Science Signaling  10 Sep 2019:
Vol. 12, Issue 598, eaap7336
DOI: 10.1126/scisignal.aap7336

Stress erythropoiesis during inflammation

Whereas steady-state erythropoiesis occurs in the bone marrow, stress erythropoiesis occurs in the spleen and liver. Hypoxia and acute anemia induce stress erythropoiesis to restore adequate numbers of red blood cells. Bennett et al. found that sterile inflammation mediated by Toll-like receptors (TLRs) induced stress erythropoiesis in mice by stimulating erythrocyte phagocytosis by splenic macrophages. This resulted in production of the transcription factor SPI-C, which cooperated with TLR signaling to induce the production of cytokines that increased the number of stress erythroid progenitors in the spleen. This work reveals a mechanism that compensates for the inhibition of steady-state erythropoiesis by proinflammatory cytokines.


Inflammation alters bone marrow hematopoiesis to favor the production of innate immune effector cells at the expense of lymphoid cells and erythrocytes. Furthermore, proinflammatory cytokines inhibit steady-state erythropoiesis, which leads to the development of anemia in diseases with chronic inflammation. Acute anemia or hypoxic stress induces stress erythropoiesis, which generates a wave of new erythrocytes to maintain erythroid homeostasis until steady-state erythropoiesis can resume. Although hypoxia-dependent signaling is a key component of stress erythropoiesis, we found that inflammation also induced stress erythropoiesis in the absence of hypoxia. Using a mouse model of sterile inflammation, we demonstrated that signaling through Toll-like receptors (TLRs) paradoxically increased the phagocytosis of erythrocytes (erythrophagocytosis) by macrophages in the spleen, which enabled expression of the heme-responsive gene encoding the transcription factor SPI-C. Increased amounts of SPI-C coupled with TLR signaling promoted the expression of Gdf15 and Bmp4, both of which encode ligands that initiate the expansion of stress erythroid progenitors (SEPs) in the spleen. Furthermore, despite their inhibition of steady-state erythropoiesis in the bone marrow, the proinflammatory cytokines TNF-α and IL-1β promoted the expansion and differentiation of SEPs in the spleen. These data suggest that inflammatory signals induce stress erythropoiesis to maintain erythroid homeostasis when inflammation inhibits steady-state erythropoiesis.

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