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 3

Conventional DCs are essential for CD24-mediated extramedullary stress erythropoiesis in vivo.

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Conventional DCs are essential for CD24-mediated extramedullary stress e...
(A–C) Stress erythropoiesis induced by αCD24 mAb treatment occurs independently of lymphocytes, granulocytes, and NK cells. Rag1–/– (A) or WT mice (B and C) were injected i.p. with 100 μg control Ig or M1/69. Ab-administrated mice were depleted of Gr-1+ granulocytes with 100 μg of anti–Gr-1 mAbs (B) or anti-Ly6G mAbs (1AG, data not shown) at day 0. To deplete NK cells, mice received 200 μg of anti-NK1.1 (PK136) mAbs at day 0 (C). The depletion efficiency of target cell type in the spleens was confirmed at day 1 by flow cytometry (top panels in B and C). One representative of the frequency of CD45–Ter119+ erythroid progenitors in spleens is shown, as measured by flow cytometry at day 5 after M1/69 treatment (A and bottom panels in B and C). Data represent mean ± SEM (n = 3–5). Cd11c-DTR mice were employed to conditionally deplete cDCs. (D) Upon i.p. DTx administration, DTR-expressing CD11c+ cells (cDC) were selectively ablated within 24 hours. (E and F) These cDC-ablated mice were infused with Ig or M1/69 4 hours after first DTx administration. Mice were necropsied at day 5 for the gross appearance of the spleens (data not shown), measurement of CD45–Ter119+ erythroid progenitors in the spleens (E), and percentage of circulating reticulocytes (F) (n = 3–5). Data represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 (2-tailed, unpaired Student’s t test). (G) Expression of CD24 among the DC subsets in the murine spleens (left panel); 2 conventional DC (cDC) subsets including CD8α+CD11b– (CD8α+ cDC, gate 1) and CD8α–CD11b+ (CD11b+ cDC, gate 2) (middle panel), and plasmacytoid DCs (CD11cintSiglecH+B220+, pDC) (data not shown). Cell surface CD24 expression was detected by flow cytometry (right panel). Representative data of at least 3 experiments are shown.