On the Non-Redundant Roles of TDO2 and IDO1

The Perspective by Pallotta et al. (1) offers the opportunity of a few more considerations on the mutually supportive relationship between tryptophan catabolic enzymes and the aryl hydrocarbon receptor (AhR) in the transitional response aimed at reinstalling homeostatic tolerance after meeting the needs of an acute inflammatory reaction (2). One major question is in fact – Why does AhR need two distinct sources of the ligand kynurenine to become activated, namely, tryptophan 2,3dioxygenase (TDO2) and indoleamine 2,3dioxygenase (IDO1) (3)? (The third known tryptophan catabolic enzyme, IDO2, has limited catalytic activity relative to the two others.). The IDO1–AhR axis would, in fact, appear to be a highly efficient mechanism per se, in that it acts in a feedforward loop [i.e., kynurenine is an activating ligand for AhR, and activated AhR promotes Ido1 transcription (4)], and it is self-regulated [AhR presides over regulatory proteolysis of IDO1, to restore homeostasis, as proposed by Pallotta et al. (1)]. For this loop to be operative, one need must be absolutely met, namely, the absence of IL-6, which operates its own mode of IDO1 proteasomal degradation via induction of SOCS3, resulting in the enzyme ubiquitination and proteolysis (5). Although it is one of AhR’s multiple jobs to transcriptionally repress FIGURE 1 | Sequential events marking the transitional response aimed at reinstalling homeostatic tolerance after meeting the needs of an acute inflammatory reaction, withTDO2 and IDO1 having temporally segregated roles.