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Review
. 2023 Jul 7;24(13):11212.
doi: 10.3390/ijms241311212.

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

Vesna Spasovski  1 , Marina Andjelkovic  1 , Marina Parezanovic  1 , Jovana Komazec  1 , Milena Ugrin  1 , Kristel Klaassen  1 , Maja Stojiljkovic  1
Affiliations
Review

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

Vesna Spasovski et al. Int J Mol Sci. .

Abstract

Systemic sclerosis (SSc) is a complex autoimmune inflammatory disorder with multiple organ involvement. Skin changes present the hallmark of SSc and coincide with poor prognosis. Interstitial lung diseases (ILD) are the most widely reported complications in SSc patients and the primary cause of death. It has been proposed that the processes of autophagy and apoptosis could play a significant role in the pathogenesis and clinical course of different autoimmune diseases, and accordingly in SSc. In this manuscript, we review the current knowledge of autophagy and apoptosis processes in the skin and lungs of patients with SSc. Profiling of markers involved in these processes in skin cells can be useful to recognize the stage of fibrosis and can be used in the clinical stratification of patients. Furthermore, the knowledge of the molecular mechanisms underlying these processes enables the repurposing of already known drugs and the development of new biological therapeutics that aim to reverse fibrosis by promoting apoptosis and regulate autophagy in personalized treatment approach. In SSc-ILD patients, the molecular signature of the lung tissues of each patient could be a distinctive criterion in order to establish the correct lung pattern, which directly impacts the course and prognosis of the disease. In this case, resolving the role of tissue-specific markers, which could be detected in the circulation using sensitive molecular methods, would be an important step toward development of non-invasive diagnostic procedures that enable early and precise diagnosis and preventing the high mortality of this rare disease.

Keywords: SSc; SSc-ILD; apoptosis; autophagy; skin fibrosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of apoptosis regulation in SSc. In the skin of SSc patients, both intrinsic and extrinsic apoptotic pathways are deregulated. In response to biochemical stimulation, both canonical and non-canonical TGF-β pathways are activated, and XIAP is shown to be a link between them. XIAP also inhibits caspase-3 and 7. As a result of constitutively activated autocrine TGFβ signaling, PP2A level is downregulated in SSc fibroblasts, leading to increased AKT and ERK1/2 phosphorylation. Extrinsic apoptotic pathway is deregulated through cIAP and XIAP proteins. Their higher expression was shown to abrogate caspase-3 and 7 in late-stage fibroblast populations from SSc patients. Matrix stiffness through the activity of fibroblast integrins transmits the mechanical force from the matrix to the actin cytoskeleton through focal adhesion-associated protein FAK. FAK activation and its constitutive phosphorylation of downstream molecules drives profibrotic gene expression. In addition, target genes regulated through this mechanism also include proapoptotic BCL-2 family members Bcl-2, BIM, and PUMA, which activate to prime the cell for apoptosis. In response to this, extensive activation of antiapoptotic Bcl-XL protein takes place, in order to ensure cell survival.
Figure 2
Figure 2
Factors that influence fibroblast-to-myofibroblast transition.
Figure 3
Figure 3
The proposed processes of apoptosis, autophagy, and cellular stress in SSc-ILD patients. Schematic representation of apoptosis, autophagy, and oxidative stress processes in SSc-ILD, where apoptosis is marked in green, autophagy in blue, and oxidative stress in orange. Downregulation of HIPK2 kinase in NSIP and p53-Mdm2 conjugate in UIP/IPF patients indicate the differences between apoptotic pathways involved in the pathogenesis of NSIP and UIP/IPF, respectively. PRDX1 is solely upregulated in NSIP-specific areas in comparison with IPF, suggesting more severe oxidative stress in IPF patients.
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