Abstract
BackgroundMacrophage migration inhibitory factor (MIF) is essential for controlling parasite burden and survival in a model of systemic Toxoplasma gondii infection. Peroral T. gondii infection induces small intestine necrosis and death in susceptible hosts, and in many aspects resembles inflammatory bowel disease (IBD). Considering the critical role of MIF in the pathogenesis of IBD, we hypothesized that MIF participates in the inflammatory response induced by oral infection with T. gondii.Methodology/Principal Findings Mif deficient (Mif−/−) and wild-type mice in the C57Bl/6 background were orally infected with T. gondii strain ME49. Mif−/− mice had reduced lethality, ileal inflammation and tissue damage despite of an increased intestinal parasite load compared to wt mice. Lack of MIF caused a reduction of TNF-α, IL-12, IFN-γ and IL-23 and an increased expression of IL-22 in ileal mucosa. Moreover, suppressed pro-inflammatory responses at the ileal mucosa observed in Mif−/− mice was not due to upregulation of IL-4, IL-10 or TGF-β. MIF also affected the expression of matrix metalloproteinase-9 (MMP-9) but not MMP-2 in the intestine of infected mice. Signs of systemic inflammation including the increased concentrations of inflammatory cytokines in the plasma and liver damage were less pronounced in Mif−/− mice compared to wild-type mice.Conclusion/SignificanceIn conclusion, our data suggested that in susceptible hosts MIF controls T. gondii infection with the cost of increasing local and systemic inflammation, tissue damage and death.
Highlights
The immune/inflammatory response to Toxoplasma gondii infection is essential to control parasite replication and tissue spread and can cause tissue damage, being descisive to pathogenesis
Given that migration inhibitory factor (MIF) regulates the expression of matrix metalloproteinase-2 (MMP) during pathological inflammatory responses such as arthritis [39,40], we investigated the possible involvement of MMP-2 and matrix metalloproteinase-9 (MMP-9) in T. gondii-induced MIF-mediated ileitis
In the present study we demonstrated that MIF increases the inflammatory response and tissue damage due to T. gondii oral infection in susceptible C57BL/6 mice
Summary
The immune/inflammatory response to Toxoplasma gondii infection is essential to control parasite replication and tissue spread and can cause tissue damage, being descisive to pathogenesis. In natural T. gondii infection through the oral route, exacerbated inflammatory responses at the small intestine (ileitis) resemble human inflammatory bowel disease (IBD) [1,7].The inflammatory response coordinate by IL-23/IL-22 is involved in T. gondii-induced disruption of intestinal homeostasis and immunopathology, an effect at least in part due to increase expression of matrix metalloproteinase-2 (MMP) [7]. These pro-inflammatory mediators and MMPs are involved in the immune pathogenesis and tissue damage in T. gondii peoral infection, increasing host morbidity and mortality despite parasite control [7,8,9]. Considering the critical role of MIF in the pathogenesis of IBD, we hypothesized that MIF participates in the inflammatory response induced by oral infection with T. gondii
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