Molecular Immunology 45 (2008) 3580–3588 Contents lists available at ScienceDirect Molecular Immunology journal homepage: www.elsevier.com/locate/molimm TLR2, TLR4 and TLR9 are differentially modulated in liver lethally injured from BALB/c and C57BL/6 mice during Trypanosoma cruzi acute infection Carrera-Silva Eugenio Antonio, Cano Roxana Carolina, Gui˜ nazu Natalia, Aoki Maria Pilar, Pellegrini Andrea, Gea Susana * Inmunologia, Departamento de Bioqu´ ımica Cl´ ınica, Facultad de Ciencias Qu´ ımicas, CIBICI-CONICET, Universidad Nacional de C´ ordoba, C´ ordoba, Argentina article info Article history: Received 28 March 2008 Received in revised form 25 April 2008 Accepted 6 May 2008 Available online 18 June 2008 Keywords: Toll-like receptor Parasite infection Inflammation Hepatic injury abstract Toll-like receptor (TLR) family is crucial for microbial elimination and homeostasis, and has an important immunoregulatory role. In this study, we comparatively analyze innate immune response and tissular injury elicited in BALB/c and C57BL/6 (B6) mice during acute Trypanosoma cruzi infection. The liver was the most affected tissue with numerous cellular infiltrates, apoptotic cells and necrotic areas. The apoptotic rate, evaluated by Hoescht stain, was highest in liver of B6. Infection increased transaminase activities in both mouse strains, although they were highest in B6. BALB/c showed sixfold higher parasitemias than B6 but the latter presented higher mortality (80%) than BALB/c (40%). To gain insight into the molecular basis, we investigated the TLRs commitment in liver. We found that, TLR2 and TLR4 were up-regulated in BALB/c while they were down-regulated in B6. However, TLR9 showed a diminution in BALB/c and an increase in B6 at the end of infection. Moreover, an intensified pro-inflammatory cytokine profile was observed in B6 and F4/80+ and Gr1+ leukocytes were the predominant cells in liver from both mouse strains. Thus, altered TLR2, TLR4 and TLR9 signalling and exacerbate inflammatory cytokine profile could be responsible of the fatal hepatic damage observed in infected B6. © 2008 Elsevier Ltd. All rights reserved. 1. Introduction The innate immune system is an evolutionally conserved host defence mechanism against pathogens. The innate immune response is initiated by pattern recognition receptors, which recog- nize specific structures of microorganisms. Among them, Toll-like receptors (TLRs) play a major role in innate immunity sensing organisms ranging from bacteria to fungi, parasites, and viruses (Uematsu and Akira, 2006). TLRs are crucial for many aspects of microbial elimination, including recruitment of phagocytes to infected tissue and sub- sequent microbial killing. However, it has been reported that, activated to excess, TLRs can mediate pathology (Akira et al., 2006). In the TLRs pathway, several transcription factors including nuclear factor (NF) kB, are activated inducing the release of pro- inflammatory cytokines, chemokines, and nitric oxide (NO) (Akira and Takeda, 2004). In addition, the activation of NF-kB by TLR sig- nalling can control the cell survival through the induction of pro- * Corresponding author at: Inmunologia, Departamento de Bioqu´ ımica Cl´ ınica, Facultad de Ciencias Qu´ ımicas, Universidad Nacional de C ´ ordoba, Ciudad Universi- taria, Haya de la Torre y Medina Allende s/n, 5000 C ´ ordoba, Argentina. Fax: +54 351 4333048. E-mail address: sgea@fcq.unc.edu.ar (S. Gea). and anti-apoptotic genes (Haase et al., 2003; Ruckdeschel et al., 2004). Recent evidence also suggests that the TLR play a role in tis- sue regeneration (Jiang et al., 2005; Seki et al., 2005; Zhang and Schluesener, 2006) as well as in the cardioprotection (Hua et al., 2007; Li et al., 2004). T. cruzi, an obligate intracellular protozoan is the causative agent of Chagas disease that affects about 20 million people and repre- sents an important public health burden in Latin America. Similar to the one found in human disease, the experimental infection of mice with trypomastigotes of T. cruzi leads to an acute infec- tion characterized by the presence of parasites in the blood and a severe immune depression. Thus, different inbred mouse strains may develop fatal or very mild infections when inoculated with the same T. cruzi isolate (Sardinha et al., 2006; Wrightsman et al., 1982) and different parasite isolates produce variable courses of infection in a given mouse strain (Andrade et al., 1985). Therefore, is clear that the interplay between host and parasite influence the outcome of this infection (Andrade et al., 1999, 2002). A progressive fatal dis- ease was recently reported in B6 mice during acute infection with Tulahu ´ en strain, which was associated with increased serum levels of TNF, a less efficient specific Ig G response, but not with a higher parasite burden (Roggero et al., 2002, 2004). When TLR-dependent pro-inflammatory pathway is triggered by infection with protozoan parasites high levels of IFN, TNF and reactive nitrogen intermediates are elicited to control the infection, 0161-5890/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.molimm.2008.05.004