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 1

Administration of αCD24 mAbs induces extramedullary stress erythropoiesis in mice.

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Administration of αCD24 mAbs induces extramedullary stress erythropoiesi...
Mice were infused i.p. with 100 μg control rat IgG2b or αCD24 mAbs (clone M1/69) and necropsied on days 1, 3, or 5 after Ab treatment. (A) Representative macroscopic appearance of spleens over time after M1/69 infusion in WT B6 mice (n > 50). (B) The rbc-lysed single-cell suspensions prepared from spleens at day 5 after Ab treatment were analyzed for cell types by flow cytometry (left panels) and enumerated (right panels, n ≥ 10): leukocyte (CD45+Ter119–, gate i); hemophagocytes (CD45+Ter119+, gate ii), and erythroid progenitor cells (CD45–Ter119+, gate iii). (C and D) Analyses of erythroblastic subsets (C) consisting of basophilic (Ter119+CD71hi, gate i, least mature), polychromatophilic (Ter119+CD71med, gate ii), and orthochromatic (Ter119+CD71lo, gate iii) erythroblasts in spleen at day 5 after treatment and reticulocytes in peripheral blood over time (n > 7, D). (E) After 2 repeated injections of M1/69 at day 0 and day 6 in Rag1–/– mice, sera were collected and measured for Hb levels at day 8 (n = 4). (F) Mice were bled at the indicated days after Ab treatment and measured for EPO levels in the sera (n = 4–6). (G) Total erythroid progenitors per spleen and BM at day 5 are depicted (n = 5). (H and I) WT and splenectomized mice were treated i.p. with control Ig or M1/69 and examined for reticulocytes in the blood (H) and erythroid progenitors in the BM (I) at day 5 after Ab treatment (n = 4–6). Data represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 (2-tailed, unpaired Student’s t test). Data are pooled from at least 2 independent experiments.