Abstract
Immunoproteasomes, harboring the active site subunits β5i/LMP7, β1i/LMP2, and β2i/MECL1 exert protective, regulatory or modulating functions during infection-induced immune responses. Immunoproteasomes are constitutively expressed in hematopoietic derived cells, constituting the first line of defense against invading pathogens. To clarify the impact of immunoproteasomes on the innate immune response against Streptococcus pneumoniae, we characterized the progression of disease and analyzed the systemic immune response in β5i/LMP7-/- mice. Our data show that β5i/LMP7 deficiency, which affected the subunit composition of proteasomes in murine macrophages and liver, was accompanied by reduced transcription of genes encoding immune modulating molecules such as pentraxins, ficolins, and collectins. The diminished opsonin expression suggested an impaired humoral immune response against invading pneumococci resulting in an aggravated systemic dissemination of S. pneumoniae in β5i/LMP7-/- mice. The impaired bacterial elimination in β5i/LMP7-/- mice was accompanied by an aggravated course of pneumonia with early mortality as a consequence of critical illness during the late phase of disease. In summary our results highlight an unsuspected role for immuno-subunits in modulating the innate immune response to extracellular bacterial infections.
Highlights
The ubiquitin proteasome system (UPS) is the primary non-lysosomal ATP-dependent protein degradation machinery in eukaryotic cells [1]
Using β5i/LMP7-/- mice, we studied the impact of i-proteasomes on the innate immune response against S. pneumoniae
Our experiments revealed that β5i/LMP7 deficiency alters the composition of proteasomes in murine macrophages and liver, which is accompanied by reduced gene transcription of immune modulating molecules
Summary
The ubiquitin proteasome system (UPS) is the primary non-lysosomal ATP-dependent protein degradation machinery in eukaryotic cells [1]. Several studies underline the role of i-proteasomes in specific pro-inflammatory signaling pathways, by controlling gene expression of immune modulators or altering the protein turnover rate of critical signaling molecules [2,9,12]. Pentraxins are cytokine-inducible soluble PRRs and part of the humoral innate immune system [25] They opsonize bacteria and promote phagocytosis by macrophages and neutrophils [26]. Using β5i/LMP7-/- mice, we studied the impact of i-proteasomes on the innate immune response against S. pneumoniae. Reduced opsonin expression and impaired bacterial elimination in β5i/LMP7-/- mice is accompanied by a more severe case of pneumonia with early mortality in consequence of critical illness during the late phase of disease. Our findings highlight an unexpected role for i-proteasomes in modulating the innate immune response to extracellular bacterial infections
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