IL-18 contributes to susceptibility to Leishmania amazonensis infection by macrophage-independent mechanisms

Abstract

We evaluated the role of IL-18 during Leishmania amazonensis infection in C57BL/6 mice, using IL-18KO mice. We showed that IL-18 is involved in susceptibility to L. amazonensis, since IL-18KO mice presented reduced lesions and parasite loads. Because macrophages are the host cells of the parasite, we investigated if macrophages were involved in IL-18-mediated susceptibility to L. amazonensis. We showed that macrophages obtained from WT or IL-18KO responded similarly to L. amazonensis infection. Moreover, we showed that C57BL/6 macrophages do not respond to IL-18, since they do not express IL-18R. Therefore, macrophages are not involved in IL-18-mediated susceptibility to L. amazonensis.

Unravelling the unsolved paradoxes of cytokine families in host resistance and susceptibility to Leishmania infection

“…However, over-expression of IL-18 exacerbates inflammation, suggesting a delicate pathophysiological role for IL-18 [17] , which has been documented in leishmaniasis. IL-18 is a susceptibility factor in CL since IL-18 -/- mice control infection compared to WT C57BL/6 mice [18] . Additionally, L. major -infected BALB/c mice treated with IL-18 showed enhanced lesions and higher Th2 responses compared to PBS-treated controls [19] .…”

Interleukin-18 Amplifies Macrophage Polarization and Morphological Alteration, Leading to Excessive Angiogenesis

“…Interleukin-18 alone influenced none of M1/M2 marker expression at concentrations from 0.1 to 200 ng/mL (Figure 2 B), high concentrations of which are used in recent papers ( 16 , 27 ). While IL-18 in the same concentration range showed no impact on alteration in M1/M2 markers induced by TNF-α (Figure 2 B), IL-18 at concentrations of 100 and 200 ng/mL but not at others significantly enhanced an increase in CD163 level (50% effective dose: 60.4 ng/mL) by IL-10, without any influence on other markers (Figure 2 B).…”

“…These differences might arise from the present result that IL-10-induced an increase in IL-18 receptor level was significantly potentiated by concomitant use of IL-18, while IL-18 alone or in combination with TNF-α had no influence (Figure 2 C). In fact, IL-18 exerts opposite functions on Mφ M1 polarization process dependent upon surrounding environmental cues ( 27 , 50 ). Additionally, the concomitant use of IL-18 had no effect on decrease in CD68 level induced by IL-10 (Figure S2C in Supplementary Material).…”

“…Data were processed using BD FACSDiva software (BD Biosciences) to determine the percentage of PI-positive dead cells in each Mφ subset. Note that the concentrations of IL-18 used in this study are appropriate for in vitro experiments as described previously ( 27 – 33 ).…”

Papel da IL-18 na resposta inflamatória contra a infecção experimental por Leishmania infantum

“…Em outro extremo, no background BALB/c (suscetível à L. major) a citocina IL-18 endógena está relacionada ao desenvolvimento de uma resposta Th2: animais NLRP3 -/-, não produtores de IL-18, e animais WT sob neutralização da IL-18 apresentam proteção contra a LC e menor expressão de IL-4, relacionada a diminuição da expressão dos fatores de transcrição GATA 3 e cMAF em células TCD4 ativadas . A IL-18 também induz a suscetibilidade durante a infecção de animais BALB/c por L. mexicana (Bryson, Wei et al 2008) e na infecção de C57BL/6 por L. amazonensis (Sousa, Carneiro et al 2015).…”