Proteasome β5i Subunit Deficiency Affects Opsonin Synthesis and Aggravates Pneumococcal Pneumonia.
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.
Institut für Biochemie, Charité Universitätsmedizin Berlin, Berlin, Germany.
Felicia
F
Kirschner
Department of Infectious Diseases and Pulmonary Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.
Katrin
K
Reppe
Institut für Biochemie, Charité Universitätsmedizin Berlin, Berlin, Germany.
Nadine
N
Andresen
Department of Infectious Diseases and Pulmonary Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.
Martin
M
Witzenrath
Institut für Biochemie, Charité Universitätsmedizin Berlin, Berlin, Germany.
Frédéric
F
Ebstein
Institut für Biochemie, Charité Universitätsmedizin Berlin, Berlin, Germany.
Peter-Michael
PM
Kloetzel
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D007155:Immunologic Factors / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009895:Opsonin Proteins / Q000378:metabolism*; D010587:Phagocytosis / Q000502:physiology; D011018:Pneumonia, Pneumococcal / Q000209:etiology* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000172:deficiency* / Q000502:physiology*; D013296:Streptococcus pneumoniae / Q000276:immunology
D016207:Cytokines; D007155:Immunologic Factors; D009895:Opsonin Proteins; D007371:Interferon-gamma; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex; C478802:Psmb5 protein, mouse