Abstract
BackgroundToll-like receptors (TLR) and cytokines play a central role in the pathogen clearance as well as in pathological processes. Recently, we reported that TLR2, TLR4 and TLR9 are differentially modulated in injured livers from BALB/c and C57BL/6 (B6) mice during Trypanosoma cruzi infection. However, the molecular and cellular mechanisms involved in local immune response remain unclear.Methodology/Principal FindingsIn this study, we demonstrate that hepatic leukocytes from infected B6 mice produced higher amounts of pro-inflammatory cytokines than BALB/c mice, whereas IL10 and TGFβ were only released by hepatic leukocytes from BALB/c. Strikingly, a higher expression of TLR2 and TLR4 was observed in hepatocytes of infected BALB/c mice. However, in infected B6 mice, the strong pro-inflammatory response was associated with a high and sustained expression of TLR9 and iNOS in leukocytes and hepatic tissue respectively. Additionally, co-expression of gp91- and p47-phox NADPH oxidase subunits were detected in liver tissue of infected B6 mice. Notably, the pre-treatment previous to infection with Pam3CSK4, TLR2-agonist, induced a significant reduction of transaminase activity levels and inflammatory foci number in livers of infected B6 mice. Moreover, lower pro-inflammatory cytokines and increased TGFβ levels were detected in purified hepatic leukocytes from TLR2-agonist pre-treated B6 mice.Conclusions/SignificanceOur results describe some of the main injurious signals involved in liver immune response during the T. cruzi acute infection. Additionally we show that the administration of Pam3CSk4, previous to infection, can attenuate the exacerbated inflammatory response of livers in B6 mice. These results could be useful to understand and design novel immune strategies in controlling liver pathologies.
Highlights
Accumulative evidences demonstrated that the liver has specific immunological properties and contains a large number of resident and non-resident cells that participate in the regulation of inflammatory and immune responses [1,2].Kupffer cells are among the first cells that orchestrate the inflammatory response under many pathological conditions and they produce pro-inflammatory cytokines and several chemokines after pathogen stimulation
Using two mouse strains with different genetic backgrounds and responses to infection, BALB/c and C57BL/6 (B6) and BALB/c, we found that infected B6 mice develop a strong pro-inflammatory environment associated with high TLR9 expression
Taking into account that the use of Toll-like receptors (TLR)-agonists is a potential therapeutic approach and a promissing strategy to treat infectious diseases [14,15,16], we evaluated if Pam3CSK4 (TLR2-TLR1 agonist) pre-treatment before challenge with T. cruzi is able to modulate the strong liver inflammatory response elicited in B6 mice
Summary
Kupffer cells are among the first cells that orchestrate the inflammatory response under many pathological conditions and they produce pro-inflammatory cytokines and several chemokines after pathogen stimulation. While TNFa and IL6 released by Kupffer cells are involved in hepatic inflammation and liver cell death, paradoxically they mediate regeneration of the liver after injury [1,3]. It has been reported that hepatocytes are desensitized by LPS in a TLR4 signalling-dependent manner [5]. LPS response is mediated by several hepatic cell populations, which are part of a cellular network involved in the hepatic wound healing and regenerative response [1,6,7]. The molecular and cellular mechanisms involved in local immune response remain unclear
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