Abstract
Apart from its role in MHC class I antigen processing, the immunoproteasome has recently been implicated in the modulation of T helper cell differentiation under polarizing conditions in vitro and in the pathogenesis of autoimmune diseases in vivo. In this study, we investigated the influence of LMP7 on T helper cell differentiation in response to the fungus Candida albicans. We observed a strong effect of ONX 0914, an LMP7-selective inhibitor of the immunoproteasome, on IFN-γ and IL-17A production by murine splenocytes and human peripheral blood mononuclear cells (PBMCs) stimulated with C. albicans in vitro. Using a murine model of systemic candidiasis, we could confirm reduced generation of IFN-γ- and IL-17A-producing cells in ONX 0914 treated mice in vivo. Interestingly, ONX 0914 treatment resulted in increased susceptibility to systemic candidiasis, which manifested at very early stages of infection. Mice treated with ONX 0914 showed markedly increased kidney and brain fungal burden which resulted in enhanced neutrophil recruitment and immunopathology. Together, these results strongly suggest a role of the immunoproteasome in promoting proinflammatory T helper cells in response to C. albicans but also in affecting the innate antifungal immunity in a T helper cell-independent manner.
Highlights
Strong inducer of Th1 and Th17 cell differentiation by the engagement of C-type lectins on the surface of antigen presenting cells and the subsequent induction of cytokines like interleukin (IL)-6, IL-12, IFN-γ, and IL-2317–20
Since Th1 and especially Th17 cells play a central role in the host defence against C. albicans, we investigated the impact of immunoproteasome inhibition on the immune response against this pathogen
In order to investigate whether LMP7 inhibition has a similar effect on human peripheral blood mononuclear cells (PBMCs), PBMCs from healthy volunteers were stimulated with heat-killed C. albicans in vitro and cytokines were measured in the supernatant by ELISA
Summary
Strong inducer of Th1 and Th17 cell differentiation by the engagement of C-type lectins on the surface of antigen presenting cells and the subsequent induction of cytokines like interleukin (IL)-6, IL-12, IFN-γ , and IL-2317–20. Th17 cells act as an important source of IL-17A which is crucial for the anti-C. albicans host defence by inducing the expression of genes encoding proinflammatory cytokines, chemokines, and antimicrobial peptides, as well as by promoting granulopoiesis and recruiting neutrophils to the site of infection[19,22,23]. Since the severity of kidney damage is quantitatively related to the levels of host innate immune responses, it has been suggested that uncontrolled inflammation and subsequent immunopathology, rather than C. albicans itself, may worsen disease outcome. We found that ONX 0914 treatment blocks Th1 and Th17 cell differentiation in response to C. albicans in vitro and in a murine model of systemic candidiasis in vivo. ONX 0914 treated mice displayed an enhanced susceptibility at early stages of infection implicating a so far undescribed influence of LMP7 inhibition on innate anti-C. albicans immune responses
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