Abstract
IntroductionThe purpose of this study was to identify differentially expressed proteins in salivary glands of the ERdj5 knockout mouse model for Sjögren’s syndrome and to elucidate possible mechanisms for the morbid phenotype development. At the same time, we describe for the first time the sexual dimorphism of the murine submandibular salivary gland at the proteome level.MethodsWe performed Liquid Chromatography/Mass Spectrometry in salivary gland tissues from both sexes of ERdj5 knockout and 129SV wildtype mice. The resulting list of proteins was evaluated with bioinformatic analysis and selected proteins were validated by western blot and immunohistochemistry and further analyzed at the transcription level by qRT-PCR.ResultsWe identified 88 deregulated proteins in females, and 55 in males in wildtype vs knockout comparisons. In both sexes, Kallikrein 1b22 was highly upregulated (fold change>25, ANOVA p<0.0001), while all other proteases of this family were either downregulated or not significantly affected by the genotype. Bioinformatic analysis revealed a possible connection with the downregulated NGF that was further validated by independent methods. Concurrently, we identified 416 proteins that were significantly different in the salivary gland proteome of wildtype female vs male mice and highlighted pathways that could be driving the strong female bias of the pathology.ConclusionOur research provides a list of novel targets and supports the involvement of an NGF-mediating proteolytic deregulation pathway as a focus point towards the better understanding of the underlying mechanism of Sjögren’s syndrome.
Highlights
The purpose of this study was to identify differentially expressed proteins in salivary glands of the ERdj5 knockout mouse model for Sjögren’s syndrome and to elucidate possible mechanisms for the morbid phenotype development
Sjögren’s syndrome (SS) is a chronic autoimmune disease that is characterised by monocellular lymphocytic infiltration in secretory tissues, such as the salivary (SG) and lachrymal (LG) glands, which results in reduced secretion of tears and saliva and has a potential for malignant lymphoma development [1, 2]
Inadequate Unfolded Protein Response (UPR) and protein misfolding may contribute to autoimmunity through four possible mechanisms: Recognition of misfolded proteins by immune cells, release of neoautoantigens by cells that are dying from unrecoverable ERstress, perturbation of immune-tolerance mechanisms and conferring of a survival advantage to autoreactive cells by upregulating ER-associated protein degradation (ERAD) proteins [10]
Summary
The purpose of this study was to identify differentially expressed proteins in salivary glands of the ERdj knockout mouse model for Sjögren’s syndrome and to elucidate possible mechanisms for the morbid phenotype development. Our recently established ER-stress related Sjögren’s syndrome animal model of ERdj knockout in mice (ERdj5-/-) strengthens this connection: ERdj is a chaperone protein involved in the ER-associated protein degradation (ERAD) pathway and its removal in mice results in the development of pathological characteristics of SS, like salivary gland inflammatory infiltrations, anti-SSA/Ro and anti-SSB/La autoantibodies, xerostomia and a marked predilection towards female individuals [8]. Two major categories of identified proteins found through this research offer a compelling model that is explored in this study: The glandular kallikrein family of serine proteases and the nerve growth factor (NGF), which is a substrate of kallikreins
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