TLR4 abrogates Th1 immune response against L. infantum infection through IRF1 and IFN-β-dependent mechanism preventing immunopathology

Abstract

Abstract Toll-like receptors (TLRs) are thought to be among the most ancient pathogen recognition systems, and these receptors directly interact with Leishmania species during the initial sensing of these parasites and mount the subsequent adaptive immune response. Herein, we aimed to evaluate the role of TLR4 during visceral leishmaniasis (VL) induced by Leishmania infantum. Initially, we observed that tlr4 messenger RNA (mRNA) expression was detected only the later stage of infection in target organs of VL, suggesting that TLR4 contributes significantly during the chronic phases of the disease. We have shown that Tlr4-deficient mice harbor fewer parasites in the spleen and liver than wild-type mice. TLR4 deficiency enhanced the Th1 immune response against the parasite, correlating with the increased activation of dendritic cells (DCs). Transcription analysis demonstrated that IRF1 and IFN-β are downstream of TLR4 after infection. Accordingly, IRF1- and IFNAR-genetically deficient mice harbored fewer parasites in the target organs than wild-type mice due to the increased Th1 response. The absence of TLR4 or IFNAR increases the serum transaminase level of infected mice. In addition, IFN-β acts directly on Th1 cells to limit IFN-γ production, without affecting the cell proliferation. Importantly, TLR4 and type I IFN (IFN-I) were positively modulated in asymptomatic subjects compared to VL patients. Thus, the TLR4-IRF1 pathway culminates in IFN-β production as a mechanism for dampening the chronic inflammatory process and preventing immunopathology development.