A Metabolic Immune Checkpoint - IL4I1

Immunometabolism, the intricate interplay between metabolic processes and the immune system, has emerged as an exciting research domain over the last decade. As immunotherapy becomes a significant therapeutic strategy in the oncology landscape, understanding the metabolic-immune checkpoints could pave the way for more effective treatments. Among several targets of interest, Interleukin-4 Induced Gene 1 (IL4I1) holds considerable promise.

Creative Biolabs delves into the function, mechanism, and therapeutic potential of IL4I1 in battling diseases such as cancer.

Introduction to IL4I1

IL4I1, a L-phenylalanine oxidase secreted by antigen-presenting cells, is involved in the metabolic regulation of immune responses. Originally identified in B cells exposed to IL-4, IL4I1 is also detectable in T cells, macrophages, dendritic cells, myeloid cells, and fibroblasts, suggesting a broader function within the immune system.

• IL4I1 serves as an immunomodulatory enzyme by catalyzing the oxidative deamination of phenylalanine and other aromatic amino acids. This metabolism produces hydrogen peroxide (H₂O₂), ammonia, and a keto-acid. The secreted hydrogen peroxide is involved in the formation of a local immunosuppressive environment that inhibits T cell proliferation and cytotoxic activity by affecting their intracellular redox state and signal transduction.
• IL4I1 may also modulate immune responses by altering the availability of amino acids like tryptophan and arginine, thereby affecting the mTOR pathway which is essential for T cell activation and differentiation.

As a metabolic checkpoint, IL4I1 takes part in the delicate balance control of the immune system, efficiently bridging metabolism and the immune responses.

Structural Insights and Metabolic Functions

The IL4I1 protein consists of a signal peptide, a copper-binding site, and a FAD-binding domain. The active site of IL4I1 contains a copper ion that plays a crucial role in its enzymatic activity. This unique structure endows IL4I1 with the ability to catalyze the oxidation of l-amino acids, particularly phenylalanine, leading to the production of reactive oxygen species (ROS) and ketoacids.

IL4I1's metabolic functions extend beyond conventional immune modulation. By depleting essential amino acids, particularly phenylalanine, IL4I1 influences T-cell proliferation and activation. Moreover, the production of ROS during the enzymatic reaction contributes to the local redox environment, further shaping the immune milieu.

Fig. 1 Regulation of the immune response by IL4I1.^1,2

IL4I1 in Autoimmunity and Cancer

• The link between IL4I1 and various autoimmune diseases, specifically those involving T cell autoimmunity, could be attributed to the suppressive effect IL4I1 exerts on T cell responses. Moreover, up-regulated IL4I1 in inflamed tissues creates an immunosuppressive local environment that hinders an effective immune response.
• The same immune suppressive characteristics of IL4I1 play an entirely different role in cancer. IL4I1 is highly expressed in many human cancers, including breast, ovarian, gastric, and melanoma, among others. The immunosuppressive metabolites of IL4I1 catalytic activity, specifically H₂O₂, aids in local immune escape, promoting tumor growth and progression. It also contributes to the protumorigenic pattern of immune cells in the tumor microenvironment, simultaneously inhibiting anti-tumor immune responses.

By co-opting metabolic pathways for suppressing immune response, IL4I1 indicates an exciting intersection of cellular metabolism and immune regulation, signifying the exploitation of metabolic checkpoints as novel therapeutic strategies. As we advance and deepen our understanding of IL4I1, we perceivably move towards the development of better, more precise immune-modulating treatments for cancer and autoimmunity.

Research into metabolic immune checkpoints such as IL4I1 is relatively nascent, yet they suggest promising avenues for innovative immunotherapies. Creative Biolabs is at the forefront of immune checkpoint research, contributing to the broader understanding and application of metabolic immune checkpoints like IL4I1.

References

1. Molinier-Frenkel, Valérie, Armelle Prévost-Blondel, and Flavia Castellano. "The IL4I1 enzyme: a new player in the immunosuppressive tumor microenvironment." Cells 8.7 (2019): 757.
2. Under Open Access license CC BY 4.0, without modification.

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