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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Research Article Immunology

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 6

The SCF/Kit signaling axis is critical for CD24-induced stress erythropoiesis at extramedullary site.

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The SCF/Kit signaling axis is critical for CD24-induced stress erythropo...
(A and B) The pharmacological inhibitor of Kit signaling, imatinib, was administrated (1 mg/kg) i.p. daily for 4 days into M1/69-treated WT mice. At day 5, reticulocytes in the blood (A) and the expansion/accumulation of CD45–Ter119+ erythroid progenitors in the spleen (B) were examined. Data represent mean ± SEM (n = 4) of 2 independent experiments. (C) WT B6 mice were treated i.p. with Kit signaling blocking Abs (clone ACK2) at days 0 and 1 (200 μg/each injection) after M1/69 treatment. In addition, Kit mutant (Kitw/Kitw–v) or controls (WBB6 background) were treated with M1/69 Abs. At day 5 after M1/69 treatment, mice were examined for percentage of reticulocytes in peripheral blood (data not shown), gross appearance of spleens (data not shown), and numbers of CD45–Ter119+ erythroid progenitors in the spleen. Data represent mean ± SEM (n = 4) combined from 2 independent experiments. ***P < 0.001. (D and E) M1/69 treatment promotes the expansion of Kit+CD45lo/–CD71+/– cells in the spleen. WT mice were injected i.p. with 100 μg control Ig or M1/69. Total Kit+CD45lo/– cells in the spleen were examined 1 day after Ab treatment (D). To determine whether Kit+CD45lo/–CD71+/– cells undergo proliferative expansion, M1/69-treated mice were fed i.p. with nucleic acid analog, BrdU, to label proliferating cells 1 hour prior to harvest. Kit+ erythroid progenitors were examined at 24 hours after Ab treatment for active uptake of BrdU (upper panels) in combination with staining for a proliferation-associated nuclear antigen, Ki-67 (bottom panels) (E). Data represent at least 3 independent experiments. (F and G) M1/69-treated WT B6 mice were i.p. injected with Kit-blocking mAbs (clone ACK2) at day 0 (200 μg). Twenty-four hours later, splenic Kit+CD45lo/– cells were examined for Ki-67 nuclear staining (F) and enumerated (G). (H) Batf3–/– mice were treated i.p. with M1/69. At day 1 after treatment, splenic Kit+CD45lo/– cells were examined and enumerated. Each symbol shown in D, G, and H represents an individual mouse; small horizontal lines indicate the mean. **P < 0.01; ***P < 0.001 (2-tailed, unpaired Student’s t test).