Current knowledge on the early stages of human neutropoiesis.

Polymorphonuclear neutrophils are no longer considered as a homogeneous population of terminally differentiated and short-lived cells that belong to the innate immune system only. In fact, data from the past decades have uncovered that neutrophils exhibit large phenotypic heterogeneity and functional versatility that render them more plastic than previously thought. Hence, their precise role as effector cells in inflammation, in immune response and in other pathophysiological processes, including tumors, needs to be better evaluated. In such a complex scenario, common knowledge of the differentiation of neutrophils in bone marrow refers to lineage precursors, starting from the still poorly defined myeloblasts, and proceeding sequentially to promyelocytes, myelocytes, metamyelocytes, band cells, segmented neutrophils, and mature neutrophils, with each progenitor stage being more mature and better characterized. Thanks to the development and utilization of cutting-edge technologies, novel information about neutrophil precursors at stages earlier than the promyelocytes, hence closer to the hematopoietic stem cells, is emerging. Accordingly, this review discusses the main findings related to the very early precursors of human neutrophils and provides our perspectives on human neutropoiesis.

Human CD34+/dim neutrophil-committed progenitors do not differentiate into neutrophil-like CXCR1+CD14+CD16- monocytes in vitro.

The advent of recent cutting-edge technologies has allowed the discovery and characterization of novel progenitors of human neutrophils, including SSCloCD66b+CD15+CD11b-CD49dhiproNeu1s, SSChiCD66b+CD15+CD11b-CD49dintproNeus2s, CD66b+CD15+CD11b+CD49d+CD101-preNeus, and Lin-CD66b+CD117+CD71+eNePs. In this research field, we recently identified CD66b-CD38+CD64dimCD115-, CD34+, and CD34dim/- cells exclusively committed to the neutrophil lineage (which we renamed as CD34+ and CD34dim/- neutrophil-committed progenitors), representing the earliest neutrophil precursors identifiable and sorted by flow cytometry. Moreover, based on their differential CD34 and CD45RA expression, we could identify 4 populations of neutrophil-committed progenitors: CD34+CD45RA-/NCP1s, CD34+CD45RA+/NCP2s, CD34dim/-CD45RA+/NCP3s, and CD34dim/-CD45RA-/NCP4s. This said, a very recent study by Ikeda and coworkers (PMID: 36862552) reported that neutrophil precursors, termed either neutrophil progenitors or "early neutrophil-committed progenitors," would generate immunosuppressive neutrophil-like CXCR1+CD14+CD16- monocytes. Hence, presuming that neutrophil progenitors/"early neutrophil-committed progenitors" correspond to neutrophil-committed progenitors, the selective neutrophil commitment that we attributed to neutrophil-committed progenitors is contradicted by Ikeda and coworkers' article. In this study, by performing a more analytical reevaluation at the phenotypic and molecular levels of the cells generated by neutrophil-committed progenitors 2 and 4 (selected as representatives of neutrophil-committed progenitors), we categorically exclude that neutrophil-committed progenitors generate neutrophil-like CXCR1+CD14+CD16- monocytes. Rather, we provide substantial evidence indicating that the cells generated by neutrophil progenitors/"early neutrophil-committed progenitors" are neutrophilic cells at a different stage of maturation, displaying moderate levels of CD14, instead of neutrophil-like CXCR1+CD14+CD16- monocytes, as pointed by Ikeda and coworkers. Hence, the conclusion that neutrophil progenitors/"early neutrophil-committed progenitors" aberrantly differentiate into neutrophil-like monocytes derives, in our opinion, from data misinterpretation.

Effects of oral wound on the neutrophil lineage in murine bone-marrow: Modulation mechanism hindered by chlorhexidine.

OBJECTIVE: The oral cavity undergoes frequent stress caused by repeated mechanical trauma, and the constant contact of the injured oral mucosa with bacteria leads to the production of various pro-inflammatory cytokines and chemokines. Neutrophils play essential roles in the acute inflammation against the invasive microbiota, and compromised neutrophil recruitment hinders the bacterial clearance and worsens periodontitis. In this study, we aimed to explore whether wounding at the oral cavity would have an impact on the neutrophil lineage, and, if so, whether microbial contamination of the wounded surface plays significant roles. METHODS: We developed a surgical model of an oral wound (palate wound), by a small incision in the hard palate of the mice. We also evaluated the effect of chlorhexidine on oral wound-induced neutrophilia of bone-marrow. RESULTS: We demonstrated an increased neutrophilia in the bone-marrow of the oral wound group, as well as decreasedex vivoneutropoietic potential, in both IL-3 and GM-CSF-driven bone-marrow cultures. Washing of the entire oral cavity with chlorhexidine before surgery abolished the bone-marrow neutrophilia in the oral wound group and increased neutropoiesis in culture, relative to the saline-treated oral wound control group. Co-located treatment (both chlorhexidine treatment and wound on the right side of the palate) resulted in significantly reduced bone-marrow neutrophilia, compared to the mismatched treatment (chlorhexidine treatment and wound on opposite sides of the palate). Neither neutrophilia nor decreased neutropoiesis were dependent on glucocorticoid signaling. CONCLUSIONS: The prophylactic use of chlorhexidine ameliorates the neutrophilic response on the bone marrow, restoring the neutrophil numbers.