Metabolic and Epigenetic States of HSC-Derived Macrophages in Autoimmune Diseases and Their Driving Mechanism of Trained Immunity

Research Background

In the context of autoimmune diseases (AD), studies have shown that prolonged activation of the immune system and inflammatory responses affect not only mature immune cells but also have profound effects on hematopoietic stem cells (HSCs). In patients with autoimmune diseases, there are large numbers of activated myeloid cells that induce the activation of autoimmune T cells through inflammatory cytokine production even without T cell receptor (TCR) stimulation, thereby exacerbating the pathological development of the disease. However, whether hematopoietic stem cells are also affected in this process and play a key role in subsequent immune responses remains an important research question.

The inflammatory state of myeloid cells present in patients with autoimmune diseases is closely related to the mechanism of “trained immunity” (TI). Trained immunity refers to the “memory” response of the innate immune system following initial exposure to a pathogen, manifesting as an enhanced immune response upon secondary exposure. This enhanced response is characterized by high-level cytokine expression and metabolic pathway reprogramming, particularly increased glycolysis and activation of the tricarboxylic acid (TCA) cycle, with the metabolic products being crucial for epigenetic reprogramming. However, whether trained immunity can be established and persist in hematopoietic stem cells and manifest similar enhanced immune functions in descendant cells remains to be further validated.

Research Source

This paper was written by Taylor S. Mills and his team members, mainly from the University of Colorado Anschutz Medical Campus and Baylor College of Medicine, among other research institutions. The study was published in the journal “Cell Stem Cell” on November 7, 2024, with Dr. Eric M. Pietras as the corresponding author.

Research Objective and Experimental Design

Research Objective

This study aims to investigate whether long-term hematopoietic stem cells (HSCslt) can act as a cell reservoir for trained immunity in autoimmune diseases, thereby exerting lasting immunoregulatory effects during the disease process. Using a murine model of systemic lupus erythematosus (SLE), the research team employed a multi-step experimental design to evaluate the metabolic and epigenetic states of macrophages derived from HSCslt in trained immunity.

Experimental Procedure

1. Impact of Autoimmune Inflammation on Myelopoiesis
   The study used a taxane-induced murine SLE model to observe the effects of chronic autoimmune inflammation on myelopoiesis by analyzing cell populations in peripheral blood and bone marrow. The results showed a significant increase in neutrophils in peripheral blood and myeloid cells in the bone marrow of taxane-treated mice, accompanied by increased inflammatory myelopoiesis.

2. Epigenetic and Metabolic Characteristics of Myeloid Progenitors and HSCs
   The research team conducted RNA sequencing and chromatin accessibility sequencing to analyze gene expression and epigenetic changes in bone marrow mononuclear cells, granulocyte-monocyte progenitors (GMP), and multipotent hematopoietic stem cells in autoimmune mice. It was found that HSCslt activated specific defense programs in the autoimmune inflammatory environment, but chromatin accessibility of metabolism-related genes was significantly reduced.

3. Transplantation Experiments on Trained Immunity Effects of HSCslt
   To validate whether HSCslt can serve as a long-term reservoir of trained immunity, the research team transplanted HSCslt from autoimmune mice into healthy mice. The results showed that transplanted HSCslt could differentiate into macrophages with enhanced antibacterial activity and cytokine secretion, and this characteristic could persist under autoimmune inflammatory conditions.

4. Metabolic State of Macrophages and Its Relationship with Functions
   The research further utilized the Seahorse analyzer to assess the metabolic characteristics of macrophages. Unlike the metabolic reprogramming observed in conventional trained immunity, HSCslt-derived macrophages displayed enhanced trained immunity features but lower activities in glycolysis and oxidative phosphorylation, indicating a decoupling between metabolism and function.

5. Chromatin Accessibility and Gene Expression Analysis
   The study found that HSCslt-induced macrophages demonstrated significantly reduced chromatin accessibility of metabolic genes under autoimmune inflammation. These epigenetic changes were primarily concentrated on core genes of glycolysis and the mTOR signaling pathway, indicating that HSCslt and their derived cells chose a low metabolic activity feature in a long-term immune memory state.

Research Results and Conclusion

Main Research Results

1. HSCslt as a Long-term Reservoir of Trained Immunity
   The experiment showed that HSCslt in an autoimmune environment could differentiate into macrophages with trained immunity features, demonstrating enhanced antibacterial activity and cytokine secretion capability. This suggests that HSCslt may become a trained immunity reservoir in autoimmune diseases.

2. Decoupling Phenomenon of Metabolism and Function
   In the trained immunity state, HSCslt-derived macrophages did not exhibit the traditional high metabolic activity, especially in glycolysis and oxidative phosphorylation, which were relatively low. Through chromatin accessibility analysis, it was found that genes related to these metabolic pathways were suppressed at the epigenetic level, indicating a significant decoupling phenomenon between metabolic regulation and functional performance.

3. Selective Maintenance of HSCslt in Autoimmune Inflammatory Environment
   The research suggests that this decoupling might be related to the selective maintenance mechanism of HSCslt under autoimmune inflammatory conditions. HSCslt in the autoimmune environment selectively maintained a low metabolic, yet immune-enhanced subset, thereby exerting sustained effects in subsequent immune responses.

Research Conclusion

The research team proposes that HSCslt, under chronic autoimmune inflammation, can act as a persistent reservoir for trained immunity, and their derived macrophages exhibit a decoupling between function and metabolism. This discovery challenges the traditional model of trained immunity, indicating that trained immunity characteristics may manifest different metabolic phenotypes in different cell sources and environments. Specifically, for HSCslt, metabolic activity is suppressed, yet they can maintain enhanced immune functions, suggesting the maintenance mechanism of trained immunity is more complex than previously thought.

Research Significance and Value

1. Expanding the Model of Trained Immunity
   This study reveals that trained immunity is not limited to myeloid progenitor cells and mature cells; long-term hematopoietic stem cells can also serve as a reservoir for trained immunity, providing a new perspective for understanding the diversity of trained immunity.

2. Implications for Metabolic Therapy in Autoimmune Diseases
   The study shows that the decoupling phenomenon of metabolism and function in HSCslt-derived macrophages might imply that targeting metabolic pathways may show different effects in trained immunity cells from different sources. This finding presents new insights for future metabolic therapy strategies in autoimmune diseases.

3. Revealing New Mechanisms in Autoimmune Disease Pathology
   HSCslt as a reservoir of trained immunity can continually activate and maintain autoimmune responses during disease remission and relapse. This mechanism suggests that HSCslt may play a key role in the recurrence of autoimmune diseases, potentially serving as a target for future treatment.

Research Highlights and Innovations

1. Innovatively Proposes the Role of HSCslt in Trained Immunity
   This study is the first to propose the role of HSCslt in trained immunity within autoimmune diseases, filling a gap in the research on trained immunity reservoirs.

2. Decoupling Phenomenon between Metabolism and Immune Function
   The research reveals a decoupling phenomenon between metabolism and function in trained immunity through epigenetic data, providing new insights into the metabolic regulatory mechanisms of the immune system.

3. Selective Maintenance Mechanism of HSCs in Long-term Autoimmune Inflammation
   This study proposes that HSCslt selectively maintain a low metabolic, immune-enhanced subset under autoimmune conditions, offering a new explanation for the pathogenesis of autoimmune diseases.

Conclusion

Through an in-depth analysis of HSCslt and their derived macrophages in an autoimmune disease model, this study reveals the potential of HSCslt as a persistent reservoir of trained immunity and the decoupling phenomenon of metabolism and function in their derivative cells. This research not only deepens the understanding of trained immunity mechanisms but also provides a theoretical basis for the metabolic therapy of autoimmune diseases. Future research will further explore whether similar decoupling phenomena exist in other disease contexts, especially in the molecular regulatory mechanisms within HSCslt, to offer new ideas for interventions in autoimmune and other chronic inflammatory diseases.