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TLRs and tryptophan metabolism at the crossroad of immunoregulatory pathways

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Volpi C., Mondanelli G., Puccetti P., Grohmann U.

vol. 1

28-50

The capacity of Toll-like receptors (TLRs) to act as pathogen sensors, to detect microorganism-derived conserved molecular structures, and to induce activation of antigen-presenting cells which secrete large amounts of type I interferons makes them attractive targets for vaccination and immunotherapeutic strategies. However, there is now considerable evidence to support that TLRs play an essential role in specific disease pathogenesis and may be novel targets for therapy. To transmit their signal to the nucleus and initiate activation of proinflammatory and antimicrobial genes, TLRs must initiate a cytoplasmic signaling cascade, which is controlled by signaling adaptors. These adaptors are crucial for activating the correct immune response to any given TLR/pathogen interaction. Disruption or improper signaling may lead to uncontrolled inflammation and the development of TLR-dependent inflammatory diseases. Indoleamine 2,3-dioxygenase 1 (IDO1) is the main tryptophan catabolic enzyme in mammals. At the intersection of the early defense mechanisms against pathogens and the complex signaling events presiding over longer-term immune homeostasis, the IFN–IDO1 axis is capable of downregulating immune responses, to minimize immune-mediated tissue and organ damage in the context of infectious immunity, infection-associated auto-immunity, and overreactive inflammatory responses. Finely tuned mechanisms regulate IDO1 functions at both the transcriptional and posttranslational levels, and IDO1 itself is a signaling molecule in a complex immune regulatory network. Recent work has revealed that the TLR9/TRIF/TRAF6 immunoregulatory pathway, which involves IRF3 and TGF-β production and is activated in plasmacytoid dendritic cells (pDCs) by high-dose CpGODN, represents a prototypic regulator that negatively controls inflammatory reaction, but positively regulates noncanonical NF-κB signaling and IDO1 induction and function. This might indicate that the modulation of TLRs could be a means through which tryptophan metabolism, when aberrant, could be controlled. More importantly, the above considerations suggest that activation of IDO1 could be a novel potential therapeutic strategy under conditions in which uncontrolled proinflammatory cytokine secretion in response to TLR signaling contributes to acute or chronic overreactive responses.

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1 Immunometabolism

1 2014

1 Grohmann U.

1 Mondanelli G.

1 Puccetti P.

1 Volpi C.

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TLRs and tryptophan metabolism at the crossroad of immunoregulatory pathways