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Stress-Associated Erythropoiesis Initiation Is Regulated by Type 1 Conventional Dendritic Cells

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Stress-Associated Erythropoiesis Initiation Is Regulated by Type 1 Conventional Dendritic Cells The Journal of Clinical Investigation RESEARCH ARTICLE Stress-associated erythropoiesis initiation is regulated by type 1 conventional dendritic cells Taeg S. Kim,1,2 Mark Hanak,1 Paul C. Trampont,3 and Thomas J. Braciale1,2,4 1Beirne B. Carter Center for Immunology Research, 2Department of Pathology, 3Department of Medicine, Division of Hematology and Oncology, and 4Department of Microbiology, University of Virginia, Charlottesville, Virginia, USA. 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. Introduction tion of reticulocyte numbers in the circulation (6, 10). In humans, Erythropoiesis is the process of production of new rbc (also the stress erythropoiesis response is believed to be localized primar- known as erythrocytes). In humans, approximately 2.4 million ily to the BM, with rbc generation in sites such as the spleen, with new erythrocytes are produced per second, normally within the associated splenomegaly only observed when stress erythropoiesis BM (1–3). Within the circulation, the end products of erythropoi- is very prominent. In contrast, in the mouse, stress erythropoiesis is esis are represented by mature rbc preceded by enucleated RNA- primarily localized to extramedullary sites such as the spleen (where containing immediate rbc precursors, the reticulocytes. After this process results in splenomegaly) and liver (typically in younger entering the circulation, mature rbc typically turn over within animals) and to a lesser extent in the BM (10–12). While stress eryth- 120 days. Erythropoiesis is therefore a dynamic process balanc- ropoiesis is generally considered to be an exaggerated form of basal ing rbc generation and clearance with the need to maintain suf- erythropoiesis and therefore dependent on the aforementioned ficient tissue oxygenation. growth factors, erythroblast progenitors and monocyte/macrophage Under homeostatic or steady-state conditions, the stable gen- lineage cells, regulators such as bone morphogenetic protein 4 eration of new rbc is orchestrated by the concerted action of certain (BMP4) and Hedgehog signaling, and the availability of self-renew- growth factors, notably erythropoietin (EPO) and the Kit ligand stem ing stress erythrocyte progenitors in these extramedullary sites have cell factor (SCF) (4–6) as well as the response of several cell types, also been implicated in the control of this process (6, 10, 13). particularly erythroid progenitors, at various states of differentiation Among the cell types within the mononuclear phagocyte sys- responding to these growth factors through measured (controlled) tem (MPS), resident (tissue) macrophages at sites of erythropoiesis proliferation, and cells of the monocyte/macrophage lineage (7). (1, 2) and, in particular, a specific subset of CD169+ macrophages In contrast to basal erythropoiesis, under conditions of inad- have been implicated as important in supporting the late-stage equate tissue oxygenation resulting from sustained hypoxia or ane- development and differentiation of erythroid progenitors into rbc, mia caused by hemorrhage or BM suppression, e.g., chemotherapy, likely through their capacity to provide soluble factors and recycled BM transplantation, infection, etc., there is a rapid response of the iron from senescent rbc and through the elimination of nuclei erythropoietic machinery to restore tissue oxygenation — a process extruded from maturing end-stage erythroid progenitors (1, 3, 14). termed stress erythropoiesis (8, 9). Stress erythropoiesis results in the In this report, we define and characterize a previously unap- rapid production of new rbc and is characterized by the rapid expan- preciated role for the mononuclear phagocytic cell lineage DCs in sion of the erythroblast progenitor pool and marked transient eleva- regulating the initiation of stress erythropoiesis through engage- ment of a stress sensor, CD24, displayed at a high level on a spe- cific subset of DCs, i.e., type 1 conventional DCs (cDC1s) (CD8 + Conflict of interest: The authors have declared that no conflict of interest exists. α + + Submitted: March 13, 2015; Accepted: August 13, 2015. in the mouse, ref. 15; and XCR1 CLEC9 in the human, refs. 16, Reference information: J Clin Invest. 2015;125(10):3965–3980. doi:10.1172/JCI81919. 17). Engagement of CD24 in vivo results in rapid early erythroid jci.org Volume 125 Number 10 October 2015 3965 RESEARCH ARTICLE The Journal of Clinical Investigation Figure 1. Administration of αCD24 mAbs induces extramedullary stress erythropoiesis in mice. 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. 3966 jci.org Volume 125 Number 10 October 2015 The Journal of Clinical Investigation RESEARCH ARTICLE progenitor expansion and associated robust transient reticulocy- administration (Figure 1G). Treatment of mice with isotype con- tosis. Animals deficient in cDC1s exhibit an impaired erythropoi- trol Abs had no effect on these parameters of hematopoietic cell etic response to hypoxemia induced by stresses including hypoxia, development or expansion. acute hemorrhage, and BM suppression. Engagement of CD24 on Engagement of CD24 in vivo had only a very modest effect the CD8α+/XCR1+CLEC9+ DCs upregulates the expression of SCF on the number of CD 45+Ter119– myeloid lineage cells in the and subsequent Kit-dependent proliferation of early erythroid pro- spleen (Figure 1B). There was a minimal impact on the frequency genitors. In parallel, CD24 engagement on CD11c+ cells stimulates and distribution of cells of the granulocytic and monocytic lin- EPO release, resulting in Kit/EPO-mediated reticulocytosis. These eages, with the exception of the Ly6Chi monocyte subset, which and related findings indicate a role for DCs operating prior to but showed a very slight incremental increase in frequency (Supple- in conjunction with macrophages and EPO in regulating an impor- mental Figure 1E). tant response of the body to injury, that is, stress erythropoiesis. The above findings suggested that engagement of CD24 in vivo induces a response within the erythroid series, which mim- Results ics stress-induced erythropoiesis. Since, in the mouse, extramed- CD24 engagement in vivo triggers extramedullary (stress–type) eryth- ullary/stress erythropoiesis is primarily localized to the spleen ropoiesis. During an analysis of the contribution of costimulation by (10), we examined the impact of splenectomy on the response to CD24 to the induction of adaptive immune CD8+ T cell responses αCD24 mAb administration. As Figure 1H demonstrates, there (18), we observed that parenteral administration of a αCD24 mAbs was a significant (~50%) reduction in circulating reticulocytes to naive mice resulted in
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