Abstract
BackgroundThe decline of proteasomal activity is known to be associated with the age-related disorders but the early events involved in this process are not apparent. To address this, we investigated the early-age-related (pediatric vs. adult) mechanisms that augment immunopathogenesis of sepsis and acute lung injury.Methodology/Principal FindingsThe 3-weeks (pediatric) and 6-months (adult) old C57BL/6 mice were selected as the study groups. Mice were subjected to 1×20 cecal ligation and puncture (CLP) mediated sepsis or intratracheal Psuedomonas aeruginosa (Pa)-LPS induced acute lung injury (ALI).We observed a significant increase in basal levels of pro-inflammatory cytokine, IL-6 and neutrophil activity marker, myeloperoxidase (MPO) in the adult mice compared to the pediatric indicating the age-related constitutive increase in inflammatory response. Next, we found that age-related decrease in PSMB6 (proteasomal subunit) expression in adult mice results in accumulation of ubiquitinated proteins that triggers the unfolded protein response (UPR). We identified that Pa-LPS induced activation of UPR modifier, p97/VCP (valosin-containing protein) in the adult mice lungs correlates with increase in Pa-LPS induced NFκB levels. Moreover, we observed a constitutive increase in p-eIF2α indicating a protective ER stress response to accumulation of ubiquitinated-proteins. We used MG-132 treatment of HBE cells as an in vitro model to standardize the efficacy of salubrinal (inhibitor of eIF2α de-phosphorylation) in controlling the accumulation of ubiquitinated proteins and the NFκB levels. Finally, we evaluated the therapeutic efficacy of salubrinal to correct proteostasis-imbalance in the adult mice based on its ability to control CLP induced IL-6 secretion or recruitment of pro-inflammatory cells.Conclusions/SignificanceOur data demonstrate the critical role of early-age-related proteostasis-imbalance as a novel mechanism that augments the NFκB mediated inflammation in sepsis and ALI. Moreover, our data suggest the therapeutic efficacy of salubrinal in restraining NFκB mediated inflammation in the adult or older subjects.
Highlights
Protein homeostasis is regulated by complex cellular processes collectively termed as ‘proteostasis’, which includes protein synthesis, folding, trafficking, disaggregation and degradation [1]
We demonstrate here the therapeutic potential of salubrinal for treating age-related disorders based on its ability to control MG-132 or cecal ligation and puncture (CLP) induced ubiquitin accumulation, endoplasmic reticulum (ER) stress and NFkB mediated inflammation, the major contributors of age-related pathological conditions
Our data indicate that VCP activity is higher in the lungs (Pa-LPS induced) and liver of adult mice compared to the pediatric as an early-age-related (Fig. 2A, B and Fig. 3D) event that may contribute to the intrinsic as well as Psuedomonas aeruginosa (Pa)-LPS/CLP mediated inflammatory signaling, NFkB activity, ER stress and apoptosis
Summary
Protein homeostasis is regulated by complex cellular processes collectively termed as ‘proteostasis’, which includes protein synthesis, folding, trafficking, disaggregation and degradation [1]. Several other functions of this system are well documented, most importantly, the regulation of important cellular signaling pathways like NFkB activation [4], cell cycle [5] and response to environmental and cellular stress [6,7]. It plays a very crucial role in the innate and adaptive immune response, by regulating antigen processing and presentation to the T cells [8].
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