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

Abstract

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 ofGdf15andBmp4, 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.

Stress Erythropoiesis is a Key Inflammatory Response

“…The ability of mice in these model systems to recover from anemia suggests that stress erythropoiesis responds differently to inflammation and can function when steady state erythropoiesis is impaired. Analysis of mice treated with zymosan A showed that stress erythropoiesis is induced within 24 h of treatment, which occurs before the mice develop anemia [41]. This observation ran counter to the prevailing models of stress erythropoiesis, which relied on hypoxia as a key inducer of stress erythropoiesis because BMP4 and Epo are hypoxia inducible genes.…”

“…Similarly, mice treated with the TLR2 ligand, zymosan A, develop a generalized inflammatory disease that is characterized by anemia that is resolved by 4 weeks after treatment. The recovery from zymosan A induced anemia is associated with increased splenic stress erythropoiesis [41,98]. These sterile inflammation models show all the hallmarks of AI, increased hepcidin expression and iron restriction, decreased steady state erythropoiesis coupled with increased myeloid output and increased erythrocyte turnover.…”

“…These initial observations demonstrated that stress erythropoiesis uses signals and progenitor cells that are distinct from steady state erythropoiesis. Further analysis using in vivo models such as erythroid short-term radioprotection-following bone marrow transplant and sterile inflammation models combined with analysis using in vitro stress erythropoiesis cultures expanded the model for stress erythropoiesis [40][41][42]. The in vitro culture system also demonstrated that human stress erythroid progenitors (SEPs) required the same signals as murine SEPs and mutations that affect murine SEP development also affect human SEP development [40,43].…”

“…Infection and inflammation from tissue damage are common occurrences, but the decrease in steady state erythropoiesis in healthy individuals is compensated so that a potentially lethal anemia is not observed. Studies in mice demonstrated that splenic erythropoiesis increases in experimental models of infection and sterile inflammation [41,[96][97][98]. Mice infected with Salmonella develop anemia, but it is compensated by increased erythropoiesis in the spleen.…”

Interplay of Heme with Macrophages in Homeostasis and Inflammation

“…On the other hand, erythrophagocytosis by spleen macrophages has been implicated in the induction of stress-erythropoiesis in this organ. Heme-driven Spi-C induction in these macrophages leads to the expression of bone morphogenic protein 4 and growth and differentiation factor 15, which in turn leads to the expansion of stress erythroid progenitors in the spleen to sustain erythropoiesis to account for the loss of steady-state erythropoiesis [81]. Collectively, the existing literature supports the notion that heme controls its own demand for erythropoiesis partially through macrophages during homeostasis and inflammation.…”