Dataset Information

Proteasome ?5i Subunit Deficiency Affects Opsonin Synthesis and Aggravates Pneumococcal Pneumonia.

ABSTRACT: Immunoproteasomes, harboring the active site subunits ?5i/LMP7, ?1i/LMP2, and ?2i/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 ?5i/LMP7-/- mice. Our data show that ?5i/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 ?5i/LMP7-/- mice. The impaired bacterial elimination in ?5i/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.

SUBMITTER: Kirschner F

PROVIDER: S-EPMC4839637 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Proteasome β5i Subunit Deficiency Affects Opsonin Synthesis and Aggravates Pneumococcal Pneumonia.

Kirschner Felicia F Reppe Katrin K Andresen Nadine N Witzenrath Martin M Ebstein Frédéric F Kloetzel Peter-Michael PM

PloS one 20160421 4

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 sy ...[more]

PMID: 27100179

Similar Datasets

Project description:Persistent myocardial hypertrophy frequently leads to heart failure (HF). Intramyocardial triacylglycerol (TAG) accumulation is closely related with cardiac remodeling and abnormal contractile function. Adipose triglyceride lipase (ATGL), a key enzyme in TAG metabolism, regulates cardiac function. However, its associated molecular pathways have not been fully defined. Here, cardiac hypertrophy and HF were induced in wild-type (WT) or ATGL knockout (KO) mice through transverse aortic constriction (TAC) for up to 4 weeks. TAC in WT mice significantly reduced cardiac function and autophagy while enhancing left ventricular hypertrophy, interstitial fibrosis, inflammatory response, superoxide generation, and cardiomyocyte apoptosis, accompanied with upregulation of the proteasome activity, reduction of PTEN level and activation of AKT-mTOR signaling, and these effects were further aggravated in ATGL KO mice. Interestingly, ATGL KO-mediated cardiac dysfunction and remodeling were markedly reversed by proteasome inhibitor (epoxomicin) or autophagic activator (rapamycin), but accelerated by PTEN inhibitor (VO-OHpic) or autophagy inhibitor 3-MA. Mechanistically, ATGL KO upregulated proteasome expression and activity, which in turn mediates PTEN degradation leading to activation of AKT-mTOR signaling and inhibition of autophagy, thereby enhancing hypertrophic remodeling and HF. In conclusion, ATGL KO contributes to TAC-induced cardiac dysfunction and adverse remodeling probably associated with the proteasome-PTEN-mTOR-autophagy pathway. Therefore, modulation of this pathway may have a therapeutic effect potential for hypertrophic heart disease. TAC-induced downregulation of ATGL results in increased proteasome (β1i/β2i/β5i) activity, which in turn promotes degradation of PTEN and activation of AKT-mTOR signaling and then inhibits autophagy and ATP production, thereby leading to cardiac hypertrophic remodeling and dysfunction. Conversely, blocking proteasome activity or activating autophagy attenuates these effects.

Project description:The ectonucleoside triphosphate diphosphohydrolase (CD39)/5' ectonuclotidase (CD73)-dependent purinergic pathway emerges as promising cancer target. Yet, except for own previous work revealing a pathogenic role of CD73 and adenosine in radiation-induced lung fibrosis, the role of purinergic signaling for radiotherapy outcome remained elusive. Here we used C57BL/6 wild-type (WT), CD39 knockout (CD39-/-), and CD73 knockout (CD73-/-) mice and hind-leg tumors of syngeneic murine Lewis lung carcinoma cells (LLC1) to elucidate how host purinergic signaling shapes the growth of LLC1 tumors to a single high-dose irradiation with 10 Gy in vivo. In complementary in vitro experiments, we examined the radiation response of LLC1 cells in combination with exogenously added ATP or adenosine, the proinflammatory and anti-inflammatory arms of purinergic signaling. Finally, we analyzed the impact of genetic loss of CD39 on pathophysiologic lung changes associated with lung fibrosis induced by a single-dose whole-thorax irradiation (WTI) with 15 Gy. Loss of CD73 in the tumor host did neither significantly affect tumor growth nor the radiation response of the CD39/CD73-negative LLC1 tumors. In contrast, LLC1 tumors exhibited a tendency to grow faster in CD39-/- mice compared to WT mice. Even more important, tumors grown in the CD39-deficient background displayed a significantly reduced tumor growth delay upon irradiation when compared to irradiated tumors grown on WT mice. CD39 deficiency caused only subtle differences in the immune compartment of irradiated LLC1 tumors compared to WT mice. Instead, we could associate the tumor growth and radioresistance-promoting effects of host CD39 deficiency to alterations in the tumor endothelial compartment. Importantly, genetic deficiency of CD39 also augmented the expression level of fibrosis-associated osteopontin in irradiated normal lungs and exacerbated radiation-induced lung fibrosis at 25 weeks after irradiation. We conclude that genetic loss of host CD39 alters the tumor microenvironment, particularly the tumor microvasculature, and thereby promotes growth and radioresistance of murine LLC1 tumors. In the normal tissue loss of host, CD39 exacerbates radiation-induced adverse late effects. The suggested beneficial roles of host CD39 on the therapeutic ratio of radiotherapy suggest that therapeutic strategies targeting CD39 in combination with radiotherapy have to be considered with caution.

Dataset Information

Proteasome ?5i Subunit Deficiency Affects Opsonin Synthesis and Aggravates Pneumococcal Pneumonia.

Publications

Proteasome β5i Subunit Deficiency Affects Opsonin Synthesis and Aggravates Pneumococcal Pneumonia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets