Nature Reviews Immunology | Regulatory Mechanisms of Stress-Adapted Myelopoiesis and Its Disease Implications

This article systematically reviews the multi-level regulatory mechanisms of emergency myelopoiesis (EM), revealing the critical roles of hematopoietic stem cells and their microenvironment interactions during infection, inflammation, and cancer, thereby providing a theoretical foundation for therapies targeting myeloid cell-related diseases.

 

Literature Overview

The article 'Made to order: Emergency myelopoiesis and demand-adapted innate immune cell production,' published in Nature Reviews Immunology, reviews and summarizes the molecular, cellular, and metabolic reprogramming mechanisms underlying emergency myelopoiesis (EM). It focuses on how hematopoietic stem and progenitor cells are mobilized under acute infections, inflammatory conditions, and within tumor microenvironments to accelerate myeloid cell production. The article also discusses the pathological persistence of this process in chronic inflammation and cancer and its contribution to disease progression. The entire section is coherent and logically structured, ending with a Chinese period.

Background Knowledge

Emergency myelopoiesis (EM) is a crucial physiological mechanism by which the host rapidly expands monocytes and neutrophils in response to infection or tissue damage. Under homeostatic conditions, hematopoietic stem cells (HSCs) maintain balanced output of multi-lineage blood cells; however, under stress conditions such as bacterial infection or chemotherapy-induced bone marrow ablation, HSCs and downstream progenitor cells undergo transcriptional, epigenetic, and metabolic reprogramming to prioritize myeloid cell differentiation to meet immune demands. Recent studies have revealed that EM is not simply an amplified version of steady-state myelopoiesis, but rather involves unique bypass mechanisms, lineage fate redirection, and activation of progenitor self-renewal programs. For example, specific MPP subpopulations can be reprogrammed by inflammatory cytokines such as IL-1, IFN-γ, and G-CSF into myeloid-biased states, while GMPs can acquire transient self-renewal capacity to form expanding clones. Additionally, stromal cells, endothelial cells, and neural signals within the bone marrow microenvironment also participate in regulating the initiation and termination of EM. However, persistent or dysregulated EM is associated with various chronic diseases such as obesity, diabetes, rheumatoid arthritis, and tumor progression, highlighting its potential value as a therapeutic target. This article systematically integrates recent advances from single-cell genomics, lineage tracing, and functional studies, offering new insights into demand-adapted hematopoiesis.

 

 

Research Methods and Experiments

The authors comprehensively analyzed recent advances in hematopoietic developmental trajectories, regulatory mechanisms of emergency myelopoiesis, and microenvironment interactions, using a range of technical approaches including single-cell transcriptomics, lineage tracing, gene knockout mouse models, bone marrow transplantation, and inflammatory stimulation models to systematically elucidate the fate regulation of HSCs and progenitor cells under various stress conditions. The study covers multiple induction models such as G-CSF, LPS, 5-FU, and Listeria infection, and compares differences in pathogen-specific myeloid responses. Furthermore, by analyzing single-cell data from bone marrow samples of human COVID-19 patients, the study validated the activation features of EM in clinical infections.

Key Conclusions and Perspectives

• Emergency myelopoiesis (EM) is a multi-layered hematopoietic reprogramming process driven by inflammatory signals, involving HSC activation, lineage bias shifts, and progenitor fate redirection
• EM is not a linear amplification of homeostatic hematopoiesis, but achieves rapid myeloid expansion through bypass mechanisms (e.g., FcyR+ MPP3 secreting IL-1/TNF-α), abnormal self-renewal of GMPs, and MPP lineage reprogramming
• Different stressors (e.g., LPS vs CpG) can selectively activate distinct monocyte production pathways, generating functionally specialized myeloid cells to combat specific pathogens
• Stromal cells in the bone marrow microenvironment (e.g., CAR cells, endothelial cells, megakaryocytes) regulate the initiation and termination of EM through secreted factors (e.g., PF4, TGF-β, IL-6)
• Chronic inflammation (e.g., obesity, arthritis) can lead to prolonged EM activation, promoting the development of comorbidities such as atherosclerosis and insulin resistance
• Tumors can hijack EM pathways to induce expansion of immunosuppressive myeloid cells, facilitating immune escape and metastasis
• In SARS-CoV-2 infection, patients exhibit EM features in the bone marrow, including GMP expansion, lymphoid contraction, and release of immature neutrophils, which correlate with disease severity

Research Significance and Prospects

This review systematically integrates the latest mechanistic advances in emergency myelopoiesis, emphasizing its dual role in infection defense and immune pathology. Future studies need to further dissect the dynamic regulatory networks governing cell fate decisions in EM, particularly the coupling mechanisms of transcription and metabolism at the single-cell level.

Targeting key nodes in EM (e.g., C/EBPβ, IRF8, Wnt/β-catenin) may offer novel strategies for controlling excessive inflammation or tumor-associated immunosuppression. Moreover, developing biomarkers capable of distinguishing physiological from pathological EM will facilitate precise interventions for related diseases.

 

 

Conclusion

This article comprehensively summarizes the regulatory network of emergency myelopoiesis and its functional significance in health and disease. As a highly adaptive immune response mechanism, EM enables rapid responses to infection and tissue injury by coordinating multi-level interactions among hematopoietic stem cells, progenitor cells, and the bone marrow microenvironment. However, under chronic inflammation or tumor conditions, sustained activation of EM can become a pathogenic driver, promoting systemic metabolic disorders, tissue damage, and immunosuppression. The article highlights several druggable nodes within the EM pathway, such as cytokine signaling (G-CSF, IL-1), transcription factors (PU.1, C/EBPβ), and metabolic reprogramming, providing a theoretical basis for developing novel immunomodulatory therapies. Furthermore, the application of single-cell technologies has revealed the critical role of HSPC heterogeneity in EM, suggesting that future therapeutic strategies should consider state-specific cellular interventions. Overall, a deeper understanding of the regulatory logic of EM not only enhances our knowledge of dynamic innate immune regulation but also offers new avenues for treating various inflammatory and neoplastic diseases.

 

James W Swann, Oakley C Olson, and Emmanuelle Passegué. Made to order: Emergency myelopoiesis and demand-adapted innate immune cell production. Nature reviews. Immunology.