As primary effector cells of the innate immune response, neutrophils exert pivotal regulatory effects on inflammatory responses at the initiation, amplification and resolution stages. This dynamic nature is apparent in multilayered signaling responses, functional plasticity and their mutual actions within the immune network. During early inflammation, neutrophils are rapidly recruited to sites of injury or infection through chemotactic axes, including the interleukin (IL)-8/C-X-C chemokine receptor (CXCR)1/2 axis and the C-X-C motif chemokine ligand 2/CXCR2 axis, as well as by pro-inflammatory cytokines such as interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α). At these sites, they destroy pathogens by phagocytosis, by producing reactive oxygen species (ROS), and through the release of so-called neutrophil extracellular traps (NETs). At the intermediate phase, activation of signaling pathways including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) leads to neutrophil activation and immunity amplification, while NETs support the equilibrium by regulating macrophage, dendritic cell, and T lymphocyte activities. Neutrophil apoptosis and subsequent macrophage-mediated efferocytosis contribute to limiting inflammatory activity and promoting tissue repair during resolution of inflammation; by contrast neutrophil-associated anti-inflammatory and pro-resolving responses, which vary according to the inflammatory context, exhibit a more complex role. Heterogeneous neutrophil populations and functional states in chronic inflammatory lesions and the tumor microenvironment (TME) may show divergent effects on tissue injury and repair. Neutrophils with primarily pro-inflammatory functions can sustain inflammation and tissue destruction, whereas neutrophils displaying anti-inflammatory or reparative programs may contribute to the repair of damaged tissues and the re-establishment of homeostasis. Together, neutrophils perform stage-specific actions across the inflammatory continuum, and their spatiotemporal fine-tuning and signal redirection could become potential targets for precise treatment of infections, autoimmunity, and tumor-related inflammation.
TXNDC11 is an endoplasmic reticulum-associated redox protein involved in protein quality control, but its relevance in acute myeloid leukemia remains incompletely understood. This study examined the expression pattern, prognostic value, and stress-related functional role of TXNDC11 in acute myeloid leukemia using public transcriptomic datasets and experimental validation. Bioinformatic analyses were used to evaluate TXNDC11 expression, survival association, protein interaction networks and pathway enrichment. Loss-of-function experiments were performed in acute myeloid leukemia cell lines to assess cell viability, oxidative stress status, endoplasmic reticulum stress signaling, and responses to the chemical chaperone 4-phenylbutyric acid. TXNDC11 expression was relatively elevated in acute myeloid leukemia samples and higher expression was associated with shorter overall survival. Protein interaction and enrichment analyses connected TXNDC11-associated networks with endoplasmic reticulum-associated degradation, unfolded protein response, endomembrane organization, and apoptosis-related pathways. In THP-1 and HL-60 cells, TXNDC11 knockdown reduced cellular viability and was accompanied by increased reactive oxygen species and malondialdehyde levels, decreased ATP content, reduced glutathione availability, and a lower GSH/GSSG ratio, indicating disruption of redox homeostasis. At the molecular level, TXNDC11 depletion increased GRP78/BiP, p-eIF2α/eIF2α, ATF4, p-IRE1α/IRE1α, cleaved ATF6 p50/full-length ATF6, DDIT3/CHOP mRNA, XBP1s mRNA, HSPA5/BiP mRNA, and cleaved caspase−3, supporting activation of multiple UPR-associated signals and apoptosis-associated marker expression. Treatment with 4-phenylbutyric acid partially attenuated these stress-related molecular and redox changes. Repeated local si-TXNDC11 administration suppressed AML xenograft growth and reduced TXNDC11 expression in endpoint tumor tissues. These findings suggest that TXNDC11 is linked to adverse prognosis in acute myeloid leukemia and may support leukemic cell stress adaptation by limiting endoplasmic reticulum stress-associated redox imbalance and apoptotic signaling.
