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2013 | 1 | 28-50

Article title

TLRs and tryptophan metabolism at the crossroad
of immunoregulatory pathways


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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.







Physical description


1 - 5 - 2014
25 - 6 - 2014
28 - 5 - 2014


  • Department of Experimental Medicine, Piazzale Gambuli, 06132
    Perugia, Italy
  • Department of Experimental
    Medicine, University of Perugia, Perugia, Italy
  • Department of Experimental
    Medicine, University of Perugia, Perugia, Italy
  • Department of Experimental Medicine, Piazzale Gambuli, 06132
    Perugia, Italy


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