Dysfunctional myeloid states in sepsis across the marrow-to-blood continuum: developmental contribution and peripheral reprogramming

Sepsis is accompanied by extensive expansion and remodeling of the myeloid compartment, yet a dysfunctional circulating phenotype does not by itself reveal where that dysfunction arose. Immature markers, low-density fractions, HLA-DR-low phenotypes, transcriptional clusters, and direct T-cell suppression describe different biological levels and carry different mechanistic implications. This review examines sepsis-associated myeloid dysfunction as a source-attribution problem across a marrow-to-blood continuum. Clinical-sepsis studies support altered hematopoietic output and lineage-specific maturation, including emergency-granulopoietic programs in circulating hematopoietic stem and progenitor cells, whereas controlled human systemic endotoxemia provides separate cross-compartment evidence of impaired monocyte maturation. In vitro , plasma from patients with sepsis can program healthy human progenitors toward suppressive myeloid states. Conversely, endotoxin tolerance, epigenetic and metabolic remodeling, activation, and degranulation can generate additional dysfunction after marrow egress. Several human observations argue against a unitary maturation-failure model. Mature CD10-positive neutrophils can suppress T-cell proliferation even when immature CD10-negative cells do not; low-density neutrophils encompass mixed maturity and activation states, and immature neutrophils are kinetically distinct from LOX-1-positive polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC)-like populations. Monocyte HLA-DR provides a further example because it functions as a dynamic immune-state readout rather than a measure of developmental maturity. Accordingly, we distinguish five evidentiary layers - hematopoietic origin, developmental state, molecular state, functional phenotype, and patient-level immune phenotype - and use them to reassess neutrophil, monocyte, and MDSC-like states. Current human evidence supports contributions from developmental remodeling and peripheral reprogramming, but their relative importance within the same lineage and patient remains unresolved. Resolving that question will require paired compartment sampling, serial multi-omics, direct functional validation, and clinically meaningful longitudinal outcomes rather than greater reliance on computational trajectories or marker-defined identities alone.