Skip to main content
. 2023 Jul 7;24(13):11212. doi: 10.3390/ijms241311212

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.