Autophagy is involved in the sclerotic phase of systemic sclerosis

Abstract

Autophagy is an essential intracellular selfdegradation system, and is known to maintain the homeostatic balance between the synthesis, degradation, and recycling of cellular proteins and organelles. Recent studies have suggested a possible role of autophagy in systemic sclerosis (SSc) ; however, differences in autophagy among pathological phases of SSc have not yet been examined. Therefore, in the current study we investigated the expression pattern of an autophagosome marker protein, microtubuleassociated protein 1 light chain 3 (LC3) in the lesional skin of a murine model and human SSc. In bleomycininduced mouse scleroderma skin, the number of LC3-positive puncta was significantly higher than that in phosphate buffered saltsinjected control skin after 4 weeks of treatment. Such an increase, however, was not observed in the skin after 2 weeks of bleomycin treatment, in which few myofibroblasts were detected. In the sclerotic phase of SSc patients, the number of LC3-positive puncta in the lower dermis was significantly higher than in the upper dermis. It was also significantly higher than in the lower dermis of the control patients. No increase in LC3-positive puncta was observed in the skin from SSc patients in edematous phase, in which myofibroblasts were hardly detected. These results suggest that changes in the autophagic degradation system reflect a skin remodeling process that leads to fibrosis.

Effects of Immunoglobulins G From Systemic Sclerosis Patients in Normal Dermal Fibroblasts: A Multi-Omics Study

“…In our study, the microtubule-associated protein 1A/1B light chain 3B (MAP1LC3B), which is a marker of the autophagosome, was overexpressed. This protein was also expressed in the skin of an SSc mouse model and patients ( 34 ). Moreover, ras-related protein 21 (a protein involved in autophagosome–lysosome fusion) was overexpressed under dcSSc ATA+ purified IgG conditions ( 35 ).…”

The multifaceted role of autophagy in skin autoimmune disorders: a guardian or culprit?

“…Malfunctional autophagy is believed to play a key role in SSc, as evidenced by the upregulation of autophagy in the fibrotic skin of SSc patients with increased expression levels of LC3, Beclin1, and ATG7, in addition to downregulated protein levels of p62 (108,139). Similarly, activation of autophagy in fibroblasts was also observed in murine models of pulmonary or dermal fibrosis, especially in the sclerotic phase compared to the edematous phase, suggesting an association between abnormal activation of the autophagic degradation system and fibrosis in SSc (139,140). Moreover, inhibition of the PI3K/Akt/mTOR signaling pathway reduced the production of the fibrotic cytokine connective tissue growth factor (CTGF) and collagen I in SSc fibroblasts via downregulation of HIF-1a (141).…”

The Role of Autophagy and Apoptosis in Affected Skin and Lungs in Patients with Systemic Sclerosis

“…Studies on skin specimens from SSc patients have shown that impaired autophagy contributes to fibrotic phenotype in this disease [ 71 , 72 , 73 ]. Namely, assessment of key autophagic molecule LC3 by immunofluorescence on skin punch biopsies of SSc patients and control samples showed higher expression of LC3 and increased autophagy in patients compared to healthy controls [ 71 ].…”

“…This finding is in concordance with results of Mori et al, who described the increased number of intracellular LC3-positive puncta in bleomycin-induced mouse scleroderma skin and in the skin of SSc patients in sclerotic phase. This result reflects autophagy activation and its potential effect on disease progression [ 73 ]. Dumit at al.…”