IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid mouse progenitors

Abstract

IntroductionHSC differentiation occurs through a series of intermediate stages, or progenitors, whereby self-renewal capacity is progressively lost and genetic programs limit the development of alternate cell lineages until commitment to a single cell type is reached. The ability to identify distinct progenitor populations via differential surface marker expression has allowed lineage potentials to be determined, and a hierarchical map of lineage restriction to be inferred. The classic model of hematopoietic development suggests that the order in which cells progress though intermediate stages, and thus the order in which developmentally restrictive programs are placed on progenitor cells to limit lineage potential, is fixed. The discovery of the common lymphoid progenitor (CLP), that yields all lymphoid cells, and the common myeloid progenitor, which propagates myeloid, erythroid, and megakaryocytic cells, provided initial evidence for the first division in the hematopoietic developmental hierarchy. 1,2 Subsequent studies, however, led to the identification of progenitors that could not easily be developmentally placed in relation to CLPs, common myeloid progenitors, and other progenitors identified in early studies. For example, in contrast to the lineage potential of common myeloid progenitors, 1,3 lymphoid-primed multipotent progenitors (LMPPs) generate lymphocytes, macrophages, and granulocytes, yet most of these cells lack the ability to generate erythrocytes and megakaryocytes at the clonal level. 4 Similarly, while granulocyte-macrophage progenitors (GMPs) generate granulocytes and macrophages in vivo and in vitro, 1 macrophage-dendritic cell (DC) progenitors (MDPs) generate macrophages and DCs, but not neutrophils. 5 These findings have generated considerable debate as to whether the existence of one progenitor precludes the existence of another progenitor that has partially overlapping developmental potential, whether multiple developmental paths lead to maturity, and whether the mature lineages that ultimately arise from different developmental routes are functionally distinct.The lineage potentials for some of the progenitors mentioned above are still in dispute because of differences in purification strategies and between findings from in vitro and in vivo assays. However, other cases in which a simple hierarchical developmental scheme cannot be applied have been unequivocally proven by multiple groups and complementary approaches. For example, while ϳ 90% of steady-state splenic DCs are thought to be derived from myeloid progenitors, transplantation, genetic tracing, and clonal in vitro assays have all demonstrated that CLPs generate ϳ 10% of the same subsets of DCs in both humans and mice, 6-13 although the continued identification of new DC subsets necessitates the validation of these findings. 14 The DCs derived from common myeloid progenitors and CLPs appear to have similar transcriptional and functional properties. 9,12,13,15 Given that the details of other stages of hematopoietic development ...

IRF8 inhibits C/EBPα activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils

“…Whether all Irf8 À / À MDPs pass through cMoPs to produce neutrophils is unknown; some Irf8 À / À MDPs may directly differentiate into neutrophils. Interestingly, Bhattacharya and colleagues 17 have recently reported that all lymphoid progenitors (ALPs) from Irf8 À / À mice can produce neutrophils. Therefore Irf8 À / À ALPs may also contribute to neutrophilia.…”

“…IRF8 is required for the generation of mouse monocytes (particularly Ly6C þ monocytes) 9,10 , classical DCs (cDCs; particularly CD8a þ DCs) and plasmacytoid DCs (pDCs) [11][12][13] that express high levels of IRF8 (refs 14,15). At the progenitor level, Irf8 À / À mice harbour increased numbers of GMPs and MDPs but lack common DC progenitors (CDPs) 16,17 . Recent studies have suggested that Irf8 transcript expression is relatively high in MDPs, CDPs and common monocyte progenitors (cMoPs) [18][19][20] .…”

Regulation of myelopoiesis by the transcription factor IRF8

“…At the progenitor level, Irf8 −/− mice accumulate MDPs but lack CDPs, CD115 − CDPs, and pre-cDCs [11,19,40]. Thus, differentiation arrest occurs between MDPs and CDPs.…”

“…We infer that the production of neutrophils from MDPs and cMoPs is a major cause of neutrophilia in Irf8 −/− mice, because these progenitors are the first populations at which IRF8 is highly expressed in the myeloid lineage. It should be mentioned that all lymphoid progenitors (ALPs) from Irf8 −/− mice can also produce neutrophils [40], and the differentiation potential of Irf8…”

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

“…[2][3][4] The differentiation and function of cDCs and pDCs is associated with specific transcriptional programs that show some overlap, such as their dependency on interferon regulatory factor 8 (IRF8), 5,6 but are mainly controlled by lineage-specific elements.…”