TLR4 abrogates the Th1 immune response through IRF1 and IFN-β to prevent immunopathology during L. infantum infection.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
AuthorsSacramento, Laís Amorim
Maruyama, Sandra Regina
Fukutani, Kiyoshi Ferreira
Cunha, Fernando Queiroz
Almeida, Roque Pacheco
da Silva, João Santana
MetadataShow full item record
AbstractA striking feature of human visceral leishmaniasis (VL) is chronic inflammation in the spleen and liver, and VL patients present increased production levels of multiple inflammatory mediators, which contribute to tissue damage and disease severity. Here, we combined an experimental model with the transcriptional profile of human VL to demonstrate that the TLR4-IFN-β pathway regulates the chronic inflammatory process and is associated with the asymptomatic form of the disease. Tlr4-deficient mice harbored fewer parasites in their spleen and liver than wild-type mice. TLR4 deficiency enhanced the Th1 immune response against the parasite, which was correlated with an increased activation of dendritic cells (DCs). Gene expression analyses demonstrated that IRF1 and IFN-β were expressed downstream of TLR4 after infection. Accordingly, IRF1- and IFNAR-deficient mice harbored fewer parasites in the target organs than wild-type mice due to having an increased Th1 immune response. However, the absence of TLR4 or IFNAR increased the serum transaminase levels in infected mice, indicating the presence of liver damage in these animals. In addition, IFN-β limits IFN-γ production by acting directly on Th1 cells. Using RNA sequencing analysis of human samples, we demonstrated that the transcriptional signature for the TLR4 and type I IFN (IFN-I) pathways was positively modulated in asymptomatic subjects compared with VL patients and thus provide direct evidence demonstrating that the TLR4-IFN-I pathway is related to the nondevelopment of the disease. In conclusion, our results demonstrate that the TLR4-IRF1 pathway culminates in IFN-β production as a mechanism for dampening the chronic inflammatory process and preventing immunopathology development.
CitationPLoS Pathog. 2020 Mar 25;16(3):e1008435. doi: 10.1371/journal.ppat.1008435. eCollection 2020 Mar.
AffiliationTWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International
- Toll-like receptor 9 signaling in dendritic cells regulates neutrophil recruitment to inflammatory foci following Leishmania infantum infection.
- Authors: Sacramento L, Trevelin SC, Nascimento MS, Lima-Jùnior DS, Costa DL, Almeida RP, Cunha FQ, Silva JS, Carregaro V
- Issue date: 2015 Dec
- Human Interleukin-32γ Plays a Protective Role in an Experimental Model of Visceral Leishmaniasis in Mice.
- Authors: Gomes RS, Silva MVT, Dos Santos JC, van Linge C, Reis JM, Teixeira MM, Pinto SA, Dorta ML, Bai X, Chan ED, Dinarello CA, Oliveira MAP, Joosten LAB, Ribeiro-Dias F
- Issue date: 2018 May
- Interleukin-27 (IL-27) Mediates Susceptibility to Visceral Leishmaniasis by Suppressing the IL-17-Neutrophil Response.
- Authors: Quirino GFS, Nascimento MSL, Davoli-Ferreira M, Sacramento LA, Lima MHF, Almeida RP, Carregaro V, Silva JS
- Issue date: 2016 Aug
- Toll-Like Receptor- and Protein Kinase R-Induced Type I Interferon Sustains Infection of Leishmania donovani in Macrophages.
- Authors: Dias BT, Goundry A, Vivarini AC, Costa TFR, Mottram JC, Lopes UG, Lima APCA
- Issue date: 2022
- Interleukin-12 augments a Th1-type immune response manifested as lymphocyte proliferation and interferon gamma production in Leishmania infantum-infected dogs.
- Authors: Strauss-Ayali D, Baneth G, Shor S, Okano F, Jaffe CL
- Issue date: 2005 Jan