Insight on the impacts of free amino acids and their metabolites on the immune system from a perspective of inborn errors of amino acid metabolism

ABSTRACT

Introduction: Amino acids (AAs) support a broad range of functions in living organisms, including several that affect the immune system. The functions of the immune system are affected when free AAs are depleted or in excess because of external factors, such as starvation, or because of genetic factors, such as inborn errors of metabolism.

Areas covered: In this review, we discuss the current insights into how free AAs affect immune responses. When possible, we make comparisons to known disease states resulting from inborn errors of metabolism, in which changed levels of AAs or AA metabolites provide insight into the impact of AAs on the human immune system in vivo. We also explore the literature describing how changes in AA levels might provide pharmaceutical targets for safe immunomodulatory treatment.

Expert opinion: The impact of free AAs on the immune system is a neglected topic in most immunology textbooks. That neglect is undeserved, because free AAs have both direct and indirect effects on the immune system. Consistent choices of pre-clinical models and better strategies for creating formulations are required to gain clinical impact.

KEYWORDS:

• Immunology
• inflammation
• inborn errors of metabolism
• anti-inflammatory therapy

Article highlights

• AAs exert several influences on the immune system, involving both pro- and anti-inflammatory mechanisms.

• Important insights into the effects of AAs have been gained from animal models, demonstrating potent anti-inflammatory effects of both free AAs and enzymes that degrade AAs, mainly through cellular effects. These effects may depend on cell type and species, however, which cautions against over interpretation from analysis of select systems.

• New insights into the biochemistry of CD18 integrin binding to glutamate suggest that under certain inflammation conditions, glutamate could regulate integrin-ligand binding and hence function of leukocytes.

• While AAs are well tolerated in general, simple enteral administration might not be successful in the dampening of inflammation because of several complex conditions.

• More carefully composed formulations of single or multiple AAs might be helpful in unleashing the potential of AAs as therapeutic agents for human inflammatory diseases.

This box summarizes key points contained in the article.

Acknowledgments

We thank Drs. Luisa Exner and Lisbeth Birk Møller for valuable suggestions on the writing of the manuscript. We thank cand. scient. Nicolas Krogh and Dr. Klaus Gregorius for inspiring discussions of AA metabolism.

Declaration of interest

M. M. Pakula is an employee of MipSalus, a biotech company currently focusing on developing a treatment of the Phenylketonuria (PKU). T. Vorup-Jensen’s laboratory collaborate with MipSalus on topics relating to treatment of PKU. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This manuscript was supported by funding from the Lundbeck Foundation, The Danish Multiple Sclerosis Association to T. Vorup-Jensen. Funding was also received by T. Vorup-Jensen and M. M. Pakula from the Innovation Fund Denmark. T. J. Maier was funded by the German Research Foundation (DFG; MA-5825/1-1) and the DFG Sonderforschungsbereich (1039/1) and is a recipient of a Heisenberg fellowship (DFG-MA-5825-2-1).