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IL-1R Type I-Dependent Hemopoietic Stem Cell Proliferation Is Necessary for Inflammatory Granulopoiesis and Reactive Neutrophilia¹

Department of Immunology, Duke University Medical Center, Durham, NC 27710

Infections and inflammation trigger neutrophilias that are supported by a hematopoietic program of accelerated granulopoiesis known as emergency granulopoiesis. The intrinsic factors that drive reactive neutrophilias and emergency granulopoiesis have been inferred but not demonstrated. Here, we show that alum cannot elicit reactive neutrophilias in IL-1R type I (IL-1RI)^–/– mice, whereas other inflammatory responses, including eosinophilia and Ab production, remain intact. Analysis of this specific impairment revealed an unanticipated role for IL-1RI in supporting increased proliferation by granulocyte/macrophage progenitors and, surprisingly, multipotent progenitors and hematopoietic stem cells (HSC). Indeed, HSC and multipotent progenitor proliferative responses were most suppressed in IL-1RI^–/– mice, suggesting a critical role for their proliferation in inflammatory granulopoiesis. Whereas IL-1 drives increased HSC proliferation directly in vitro, IL-1RI expression by radiation-resistant host cells was both necessary and sufficient for alum-induced HSC, multipotent progenitor, and granulocyte/macrophage progenitor proliferation and reactive neutrophilias in radiation chimeric mice. Thus, IL-1 plays a necessary, but indirect, role in the support of alum-induced neutrophilias by expanding both pluripotent and myeloid progenitor compartments to accelerate granulopoiesis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI24335 and AI56363 (to G.K.) and AI56123 and CA98129 (to M.K.).

² Y.U. and D.W.C. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Garnett Kelsoe, Department of Immunology, Duke University, Durham, NC 27710. E-mail address: ghkelsoe{at}duke.edu

⁴ Abbreviations used in this paper: BM, bone marrow; C/EBP, CCAAT enhancer-binding protein; CFU-GEMM, CFU-granulocyte/erythroblast/macrophage/megakaryocyte; CFU-GM, CFU-granulocyte/macrophage; CGG, chicken -globulin; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; GMP, granulocyte/macrophage progenitor; HSC, hematopoietic stem cell; IL-1RI, IL-1R type I; KO, knockout; MEP, megakaryocyte/erythroid progenitor; MPP, multipotent progenitor; NP, (4-hydroxy-3-nitrophenyl)acetyl; SCF, stem cell factor; WT, wild type.

⁵ The online version of this article contains supplemental material.