Stress-associated erythropoiesis initiation is regulated by type 1 conventional dendritic cells
Taeg S. Kim, … , Paul C. Trampont, Thomas J. Braciale
Taeg S. Kim, … , Paul C. Trampont, Thomas J. Braciale
Published September 21, 2015
Citation Information: J Clin Invest. 2015;125(10):3965-3980. https://doi.org/10.1172/JCI81919.
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Stress-associated erythropoiesis initiation is regulated by type 1 conventional dendritic cells

Abstract

Erythropoiesis is an important response to certain types of stress, including hypoxia, hemorrhage, bone marrow suppression, and anemia, that result in inadequate tissue oxygenation. This stress-induced erythropoiesis is distinct from basal red blood cell generation; however, neither the cellular nor the molecular factors that regulate this process are fully understood. Here, we report that type 1 conventional dendritic cells (cDC1s), which are defined by expression of CD8α in the mouse and XCR1 and CLEC9 in humans, are critical for induction of erythropoiesis in response to stress. Specifically, using murine models, we determined that engagement of a stress sensor, CD24, on cDC1s upregulates expression of the Kit ligand stem cell factor on these cells. The increased expression of stem cell factor resulted in Kit-mediated proliferative expansion of early erythroid progenitors and, ultimately, transient reticulocytosis in the circulation. Moreover, this stress response was triggered in part by alarmin recognition and was blunted in CD24 sensor– and CD8α+ DC-deficient animals. The contribution of the cDC1 subset to the initiation of stress erythropoiesis was distinct from the well-recognized role of macrophages in supporting late erythroid maturation. Together, these findings offer insight into the mechanism of stress erythropoiesis and into disorders of erythrocyte generation associated with stress.

Authors

Taeg S. Kim, Mark Hanak, Paul C. Trampont, Thomas J. Braciale

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Figure 4

CD24+CD8α+ DCs regulate the initiation of CD24-mediated stress erythropoiesis.

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CD24+CD8α+ DCs regulate the initiation of CD24-mediated stress erythropo...
(A) Mice lacking transcriptional factor Batf3 gene (Batf3–/– mice) were examined for the selective deficiency of CD8α+ cDC subsets in the spleen. (B and C) WT and Batf3–/– mice were injected i.p. with 100 μg control Ig or M1/69. After 5 days, the percentage of reticulocytes in the blood (B) and absolute number of CD45–Ter119+ erythroid progenitors in the spleens (C) were assessed by flow cytometry (n = 4–6). Data represent mean ± SEM. *P < 0.05; ***P < 0.001 (Student’s t test). (D) BMDCs prepared from either WT or Cd24–/– mice were transferred i.v. into Cd24–/– mice prior to αCD24 mAb (M1/69) treatment. At day 5 after treatment, late erythroid progenitors (CD45–Ter119+) in the spleens were enumerated (n = 4–5/group). ***P < 0.001. (E) cDC in DTR Tg mice were conditionally and selectively eliminated at the indicated days after M1/69 treatment. These cDC-ablated, Ab-treated mice were necropsied at day 5 for the measurement of CD45–Ter119+ erythroid progenitors in the spleens. Data shown are representative of at least 3 independent experiments. (F) Phagocytic cells were eliminated in vivo by clodronate liposome administration at the indicated days after M1/69 treatment. These phagocyte-depleted, Ab-treated mice were necropsied at day 5 for the measurement of CD45–Ter119+ erythroid progenitors in the spleen by flow cytometric analyses. Data shown are representative of at least 3 independent experiments.