Several metabolites of the kynurenine pathway have been shown to have immunomodulatory effects through various mechanisms. To name a few: (1) the tryptophan depletion theory, where activation of the kynurenine pathway via IDO-1 prevents graft rejection by suppressing T-cells—highlighting the importance of the KP in immune regulation in autoimmunity and cancer immune biology; (2) the KYN-AhR pathway, which contributes to our understanding of immune tolerance against infection; and (3) new mechanistic insights into immunoregulation by neuroactive KP metabolites, such as KA (via GPR35) and QA (via Foxo-1-PPARγ, featured in March 2023). A new addition to the field is 3-hydroxykynurenine (3-HK), which can promote defense against infection via kainate receptors.
Dr. Margarita Parada-Kusz and colleagues showed that Salmonella can downregulate host KP activity, particularly 3-HK, to promote its survival. They also demonstrated that 3-HK upregulates kainate-sensitive glutamate receptors, which is an important mechanism against infection caused by Salmonella. Consequently, exogenous treatment with 3-HK confers protection and survival of zebrafish against lethal infection in the presence of macrophages. This study demonstrates that the effects are unique to 3-HK and its interaction with kainate receptors in Salmonella infection, not overlapping with other immunomodulatory KP metabolites or KP-associated immune modulatory mechanisms.
Although the authors note that 3-HK does not work as an antibiotic, its novel mode of action in targeting Salmonella infection by acting on the host immune system is noteworthy. Taken together with other immune-modulatory KP metabolites, these findings demonstrate the complexity and diversity of the KP in host-pathogen dynamics. It will be interesting to investigate how immune modulation and metabolic programming of this pathway can impact future health outcomes. For example, a previous study (see March 2024) showed that 3-HK supplementation is associated with a shortened lifespan of Drosophila. This suggests the need to pay special attention to the intricate balance of tryptophan metabolism (both intra- and inter-species) in future research.