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TLRs and tryptophan metabolism at the crossroad of immunoregulatory pathways

100%

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.

Receptory rozpoznające wirusowe kwasy nukleinowe w odpowiedzi przeciwwirusowej ryb

71%

Rakus K., Chadzińska M.

Kosmos

2017

vol. 66

issue 4

609-621

Kluczowym etapem nieswoistej reakcji odpornościowej organizmu na zakażenie wirusowe jest szybkie wykrycie obecności wirusów w komórce i aktywacja syntezy interferonów (IFN) typu I. Wirusowe kwasy nukleinowe (DNA i RNA) są głównymi strukturami pochodzenia wirusowego rozpoznawanymi przez receptory wrodzonego układu odpornościowego. Wśród receptorów rozpoznających te struktury bardzo istotną rolę odgrywają receptory Toll-podobne (TLR) i RIG-I-podobne (RLR). Wiele z tych receptorów opisanych u ssaków występuje także u ryb, chociaż z drugiej strony ryby posiadają także receptory, które nie zostały zidentyfikowane u ssaków. Ryby, które są pierwszymi kręgowcami z pełni rozwiniętym układem odpornościowym wrodzonym i nabytym, stanowią doskonały model do badania ewolucji mechanizmów odporności u kręgowców. W pracy przedstawiono receptory rozpoznające wirusowe kwasy nukleinowe opisane u ryb oraz główne białka adaptorowe biorące udział w przekazywaniu sygnału wewnątrzkomórkowego w celu aktywacji syntezy IFN typu I i cytokin prozapalnych.

Recognition of the non-self signature of invading viruses is a crucial step for the initiation of the anti-viral innate immune defense mechanisms including interferon (IFN) type I production. Viral nucleic acids occur the main virus-derived structures to be recognized by the receptors of the innate immune system. There are a number of receptors that recognize viral nucleic acids among which the most important are Toll-like receptors (TLR) and RIG-I-like receptors (RLR). Many of those receptors described in mammals have been also found in fish, although fish possess some specific receptors which have not been characterized in mammals. Teleost fish represent a relevant model for the study of the core immune mechanisms activated by viral infections. In this work we review the current knowledge about the fish receptors for viral nucleic acids and the main adaptor proteins involved in signaling pathways for the activation IFN type I and pro-inflammatory cytokine synthesis.

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1 Immunometabolism

1 Kosmos

1 2017

1 2014

1 Chadzińska M.

1 Grohmann U.

1 Mondanelli G.

1 Puccetti P.

1 Rakus K.

1 Volpi C.

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TLRs and tryptophan metabolism at the crossroad of immunoregulatory pathways

Receptory rozpoznające wirusowe kwasy nukleinowe w odpowiedzi przeciwwirusowej ryb