TLR4 abrogates the Th1 immune response through IRF1 and IFN-β to prevent immunopathology during L. infantum infection

Abstract

A 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

TF–RBP–AS Triplet Analysis Reveals the Mechanisms of Aberrant Alternative Splicing Events in Kidney Cancer: Implications for Their Possible Clinical Use as Prognostic and Therapeutic Biomarkers

“…The NFKB2 and UBE2D2 genes are related to TLR4. The TLR4 gene plays a fundamental role in pathogen recognition and the activation of innate immunity, is required for IRF1 expression, and the TLR4-IRF1 pathway plays important roles in many diseases [57,58]. UBE2D2 inhibits the expression of IRF1, while NFKB2 promotes the expression of IRF1.…”

Epidemiologic, Clinical and Immunological Consequences of Co-Infections during Canine Leishmaniosis

“…In a mouse model of fatal ehrlichiosis, Ehrlichia induced strong pro-inflammatory responses via activation of inflammasomes, which promoted production of IL-1β and Type I IFNs [ 116 ]. Some mouse model studies demonstrated that production of Type I IFNs, IFN-α and IFN-β, led to impaired Th1 cell responses during visceral leishmaniasis [ 117 , 118 ]. Type I IFN production by Ehrlichia co-infected macrophages may impact immune responses against L. infantum in infected dogs and then prompt disease progression.…”

“…However, Type I IFN signaling is likely to be modulated during visceral leishmaniasis. In an infection model, L. infantum induced Type I IFN expression in conventional dendritic cells in vivo, which lead to an impaired Th1 cell response [ 118 ]. Recently, Kumar et al found high levels of IFN-α, IFN-β, and their receptors in PBMCs from visceral leishmaniasis patients before drug treatment relative to post-treated VL patients and endemic controls [ 117 ].…”

Context Is Key: Delineating the Unique Functions of IFNα and IFNβ in Disease

“…Overall, parasitic pathogens are biologically very diverse, so data from other parasitic infection models are needed to begin drawing broad conclusions. A recent study demonstrated that the TLR4-IRF1-IFNβ axis played a protective role in mice infected with Leishmania infantum by dampening proinflammatory pathways and IFNγ production by CD4 + T cells ( 218 ). RNA sequencing analysis of human samples revealed that upregulation of TLR4 and type I IFN pathways was associated with asymptomatic individuals compared to patients with visceral leishmaniasis ( 218 ).…”

“…A recent study demonstrated that the TLR4-IRF1-IFNβ axis played a protective role in mice infected with Leishmania infantum by dampening proinflammatory pathways and IFNγ production by CD4 + T cells ( 218 ). RNA sequencing analysis of human samples revealed that upregulation of TLR4 and type I IFN pathways was associated with asymptomatic individuals compared to patients with visceral leishmaniasis ( 218 ). Another group found that Ifnar1 −/− mice were more susceptible to Toxoplasma gondii infection ( 219 ).…”