Inhibiting the immunoproteasome exacerbates the pathogenesis of systemic Candida albicans infection in mice

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.

Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1

“…Precisely how the ubiquitin-proteasomal degradative pathway is activated by DAPK1 to inhibit NLRP3, and whether the activation of the immunoproteasome by IFN-γ (Aki et al., 1994) is also involved, remains to be determined. It is nevertheless of interest that the ankyrin repeats of DAPK1 may bind E3 ubiquitin ligases (Jin et al., 2002) and that the immunoproteasome is implicated in fungal pathogenicity (Mundt et al., 2016) and lung responses to infections (Keller et al., 2015). …”

Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy

“…We observed that ONX-0914 treatment positively modulates fibrosis in chronic mice, suggesting that the increase in strength could be determined by amelioration of muscular architecture that improved the efficacy of myofibers contraction. Therefore, taking into consideration that ONX-0914 not only affects T helper cells (Th1 and Th17) but interestingly also antigen presenting innate immune cells (iNKT, γδT-cells, and innate lymphoid cells) 48 further studies are needed to fully understand i-proteasome role in muscular pathways. In this sense Chen et al demonstrated an involvement of i-proteasome in macrophages polarization in lung tissue.…”

The immunoproteasome‐specific inhibitor ONX 0914 reverses susceptibility to acute viral myocarditis

“…Furthermore, the ONX 0914 analog KZR‐616 has only recently entered clinical development phase I/II trials treating patients with autoimmune‐triggered inflammation. These studies are based on the highly regulated immunoproteasome function of controlling cytokine production and antigen presentation (Muchamuel et al , ; Basler et al , , ; Groettrup et al , ; Kalim et al , ; Mundt et al , ), which is in turn intensively influenced through its inhibition.…”