Abstract
Autophagy has a large range of physiological functions and its dysregulation contributes to several human disorders, including autoinflammatory/autoimmune diseases such as inflammatory myopathies (IIMs). In order to better understand the pathogenetic mechanisms of these muscular disorders, we sought to define the role of autophagic processes and their relation with the innate immune system in the three main subtypes of IIM, specifically sporadic inclusion body myositis (sIBM), polymyositis (PM), dermatomyositis (DM) and juvenile dermatomyositis (JDM). We found that although the mRNA transcript levels of the autophagy-related genes BECN1, ATG5 and FBXO32 were similar in IIM and controls, autophagy activation in all IIM subgroups was suggested by immunoblotting results and confirmed by immunofluorescence. TLR4 and TLR3, two potent inducers of autophagy, were highly increased in IIM, with TLR4 transcripts significantly more expressed in PM and DM than in JDM, sIBM and controls, and TLR3 transcripts highly up-regulated in all IIM subgroups compared to controls. Co-localization between autophagic marker, LC3, and TLR4 and TLR3 was observed not only in sIBM but also in PM, DM and JDM muscle tissues. Furthermore, a highly association with the autophagic processes was observed in all IIM subgroups also for some TLR4 ligands, endogenous and bacterial HSP60, other than the high-mobility group box 1 (HMGB1). These findings indicate that autophagic processes are active not only in sIBM but also in PM, DM and JDM, probably in response to an exogenous or endogenous ‘danger signal’. However, autophagic activation and regulation, and also interaction with the innate immune system, differ in each type of IIM. Better understanding of these differences may lead to new therapies for the different IIM types.
Highlights
Macroautophagy is a ubiquitous intracellular catabolic process in which a targeted portion of cytoplasm is enclosed in a double membrane to become an autophagosome, which subsequently fuses with a lysosome
The results of quantitative real-time PCR for PM, sporadic inclusion body myositis (sIBM), DM, juvenile dermatomyositis (JDM), and controls are shown in Figure 1. mRNA levels of beclin1, mammalian ortholog of yeast Atg6 responsible for phagophore development [1,23] were similar in idiopathic inflammatory myopathies (IIMs) and controls
Consistent with recent findings [17,18,19,20], TLR4 transcripts were significantly upregulated in PM (P,0.01) and DM (P,0.001) compared to controls, but not in sIBM or JDM
Summary
Macroautophagy (or autophagocytosis) is a ubiquitous intracellular catabolic process in which a targeted portion of cytoplasm is enclosed in a double membrane to become an autophagosome, which subsequently fuses with a lysosome. Autophagy contributes to the degradation of intracellular pathogens, modulates major histocompatibility complex class II (MHC II)-restricted endogenous antigen presentation, is an effector of Thelper 1 (Th1)/Th2 cell polarization, influences B- and T-cell homeostasis and repertoire selection, and assists pattern recognition receptors by delivering pathogen-associated molecular patterns from the cytosol to endosomal Toll-like receptors (TLRs) [6] Since autophagy has such a large range of physiological functions, it is unsurprising that its dysregulation contributes to several human diseases, including cardiac dysfunction, diabetes, neurodegenerative disorders (Huntington’s, Alzheimer’s and Parkinson’s diseases), cancer, and autoinflammatory/autoimmune diseases [7], including sporadic inclusion body myositis (sIBM) [8,9,10], in which it seems to be responsible for the accumulation of the multiple protein aggregates characteristic of the muscle fibers of this disease [8]. Based on evidence of TLR involvement in autophagy [11,12,13,14,15,16] and findings that these receptors are implicated in the pathogenesis of IIMs [17,18,19,20], we investigated relations between autophagy and TLRs and other molecules of innate immunity, in PM, DM, JDM, and sIBM
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
