title: Inflammation triggers emergency granulopoiesis through a density-dependent feedback mechanism.
abstract: Normally, neutrophil pools are maintained by homeostatic mechanisms that require the transcription factor C/EBPα. Inflammation, however, induces neutrophilia through a distinct pathway of "emergency" granulopoiesis that is dependent on C/EBPβ. Here, we show in mice that alum triggers emergency granulopoiesis through the IL-1RI-dependent induction of G-CSF. G-CSF/G-CSF-R neutralization impairs proliferative responses of hematopoietic stem and progenitor cells (HSPC) to alum, but also abrogates the acute mobilization of BM neutrophils, raising the possibility that HSPC responses to inflammation are an indirect result of the exhaustion of BM neutrophil stores. The induction of neutropenia, via depletion with Gr-1 mAb or myeloid-specific ablation of Mcl-1, elicits G-CSF via an IL-1RI-independent pathway, stimulating granulopoietic responses indistinguishable from those induced by adjuvant. Notably, C/EBPβ, thought to be necessary for enhanced generative capacity of BM, is dispensable for increased proliferation of HSPC to alum or neutropenia, but plays a role in terminal neutrophil differentiation during granulopoietic recovery. We conclude that alum elicits a transient increase in G-CSF production via IL-1RI for the mobilization of BM neutrophils, but density-dependent feedback sustains G-CSF for accelerated granulopoiesis.
authors.affiliation: Department of Immunology, Duke University, Durham, North Carolina, United States of America.
authors.forename: Derek W
authors.initials: DW
authors.lastname: Cain
authors.forename: Pilar B
authors.initials: PB
authors.lastname: Snowden
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Sempowski
authors.forename: Garnett
authors.initials: G
authors.lastname: Kelsoe
mesh_terms: D000534:Alum Compounds / Q000633:toxicity; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood*; D006098:Granulocytes / Q000276:immunology* / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000276:immunology*; D019891:Leukopoiesis / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced / Q000276:immunology
chemical_list: D000534:Alum Compounds; D016179:Granulocyte Colony-Stimulating Factor; C041524:aluminum sulfate