Role of Hypoxia and HIF Signaling in Immunometabolism

Shizhang Reicher^*
*Correspondence: Shizhang Reicher, Department of Immunology, Nanjing University, Nanjing, China, Email:

Keywords

Hypoxia • HIF signalling • Immunometabolism • Immune cells • Metabolic reprogramming • Immune-related disorders • Therapeutic targets

Introduction

The immune system is a remarkable network of cells and molecules that protects the body against invading pathogens, while also maintaining tolerance to self. To execute these functions, immune cells constantly adapt their metabolic pathways to meet the energy and biosynthetic demands of their effector functions. This intersection of immunology and metabolism has given rise to the field of immunometabolism, which investigates how immune cell function is influenced by cellular metabolism. Hypoxia, a condition characterized by reduced oxygen levels, is a common microenvironmental feature encountered by immune cells during infection, inflammation and in certain pathological conditions like solid tumors. Cells exposed to hypoxia need to rapidly adjust their metabolic processes to ensure survival and maintain their immune functions. One key player in this adaptation is the Hypoxia-Inducible Factor (HIF) family of transcription factors.

When oxygen levels drop, immune cells must shift their metabolic strategies to generate ATP (adenosine triphosphate), the cellular energy currency, more efficiently. One of the most pronounced metabolic changes in hypoxic immune cells is the shift from Oxidative Phosphorylation (OXPHOS) to glycolysis for ATP production, known as the Warburg effect. This shift allows cells to produce ATP even under oxygen-deprived conditions, but it comes at the cost of reduced efficiency. During hypoxia, immune cells, such as T cells and macrophages, upregulate glucose transporters and enzymes involved in glycolysis to meet their energy demands. Additionally, hypoxia promotes the stabilization and activation of HIFs, which further modulate immune cell metabolism [1].

Literature Review

Genetic engineering of immune cells, such as Chimeric Antigen Receptor (CAR) T cells, can benefit from an improved understanding of immunometabolism. Tailoring the metabolic profiles of these engineered cells may enhance their therapeutic potential. Translating the findings from preclinical studies into clinical trials is crucial for validating the therapeutic potential of targeting hypoxia and HIF signalling. HIFs are transcription factors that govern the cellular response to hypoxia. The HIF family includes HIF- 1α, HIF-2α and HIF-3α, with HIF-1α being the most extensively studied in the context of immunometabolism. HIF-1α plays a central role in metabolic reprogramming during hypoxia. It enhances glycolysis by upregulating the expression of glycolytic enzymes and glucose transporters, ensuring an adequate energy supply for immune cells. Furthermore, HIF-1α inhibits mitochondrial respiration and the production of Reactive Oxygen Species (ROS) to reduce oxidative damage in hypoxic environments [2].

Dysregulated HIF signaling in immune cells has been implicated in various immune-related disorders. For instance, in cancer, the tumor microenvironment often features hypoxia and aberrant HIF activation. This can lead to immune suppression, as HIF-1α-driven metabolic changes favor the development of immunosuppressive immune cell populations and reduce the cytotoxic activity of T cells. Inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, also exhibit dysregulated HIF signalling, which contributes to chronic inflammation and tissue damage. Understanding the role of HIFs in these disorders opens new avenues for therapeutic intervention [3].

The connection between hypoxia, HIF signalling and immunometabolism presents exciting opportunities for therapeutic development. Modulating HIF activity and the metabolic pathways it controls could potentially enhance the effectiveness of immunotherapies, boost immune responses in hypoxic tumor microenvironments and ameliorate chronic inflammatory conditions. The intricate relationship between hypoxia, HIF signalling and immunometabolism underscores the importance of considering metabolic reprogramming as a crucial aspect of immune cell function. Future research in this field will likely uncover novel therapeutic targets and strategies for immune-related diseases, ultimately improving the treatment options available for patients with immune disorders [4].

Discussion

The role of hypoxia and HIF signaling in immunometabolism continues to grow, several avenues of research and potential applications emerge. Developing drugs that selectively modulate HIF activity in immune cells holds promise for treating immune-related disorders. Small molecule inhibitors or activators of HIF signaling pathways could be designed to fine-tune immune responses in specific disease contexts. Harnessing the knowledge of immunometabolism in hypoxic environments, researchers are exploring the development of metabolic immunotherapies. These therapies aim to boost the immune system's ability to fight cancer by enhancing the metabolic fitness of immune cells within the tumor microenvironment [5].

Understanding how different immune cell populations respond to hypoxia and HIF signaling may lead to personalized treatment strategies. Tailoring therapies based on an individual's immune cell metabolism could improve treatment outcomes while minimizing side effects. Investigating how hypoxia and HIFs influence the formation and maintenance of immune memory is essential for improving vaccination strategies. This knowledge can help design more effective vaccines that generate long-lasting immune protection. Identifying metabolic biomarkers associated with HIF signaling in immune cells can aid in disease diagnosis and prognosis. Such biomarkers could serve as indicators of disease severity or treatment response. Combinatorial approaches that integrate immunotherapy, metabolic interventions and traditional treatments may prove highly effective in challenging diseases like cancer. Synergistic effects between these approaches could enhance patient outcomes [6].

Conclusion

The role of hypoxia and HIF signaling in immunometabolism is an exciting and rapidly evolving area of research. It highlights the profound impact that oxygen levels and metabolic reprogramming have on immune cell function and immune-related disorders. Understanding these intricate connections offers new avenues for therapeutic intervention, with the potential to revolutionize the treatment of diseases ranging from cancer to autoimmune conditions. As researchers continue to unravel the complexities of immunometabolism, we can look forward to innovative approaches that harness the power of metabolism to enhance immune responses and improve patient outcomes. The field of immunometabolism, with a particular focus on the influence of hypoxia and HIF signaling, is poised to transform our understanding of immune system function and open new doors to innovative therapies. It is an exciting time for researchers, clinicians and patients alike as we explore the immense potential that lies at the intersection of immunology and metabolism.

Acknowledgement

We thank the anonymous reviewers for their constructive criticisms of the manuscript.

Conflict of Interest

The author declares there is no conflict of interest associated with this manuscript.

References

1. Plastira, Ioanna, Eva Bernhart, Lisha Joshi and Chintan N. Koyani, et al. "MAPK signaling determines Lysophosphatidic Acid (LPA)-induced inflammation in microglia." J Neuroinflammation 17 (2020): 1-17.

Google Scholar, Crossref, Indexed at

2. Bernier, Louis-Philippe, Elisa M. York and Brian A. MacVicar. "Immunometabolism in the brain: How metabolism shapes microglial function." Trends Neurosci 43 (2020): 854-869.

Google Scholar, Crossref, Indexed at

3. Lynch, Marina A. "Can the emerging field of immunometabolism provide insights into neuroinflammation?." Prog Neurobiol 184 (2020): 101719.

Google Scholar, Crossref, Indexed at

4. O'Neill, Luke AJ, Rigel J. Kishton and Jeff Rathmell. "A guide to immunometabolism for immunologists." Nat Rev Immunol 16 (2016): 553-565.

Google Scholar, Crossref, Indexed at

5. Radhakrishnan, Rangasudhagar, Ji Hee Ha, Muralidharan Jayaraman and Jinsong Liu, et al. "Ovarian cancer cell-derived lysophosphatidic acid induces glycolytic shift and cancer-associated fibroblast-phenotype in normal and peritumoral fibroblasts." Cancer Lett 442 (2019): 464-474.

Google Scholar, Crossref, Indexed at

6. Lin, Michael T. and M. Flint Beal. "Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases." Nature 443 (2006): 787-795.

Google Scholar, Crossref, Indexed at