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Gasdermine E-Dependent Mitochondrial Pyroptotic Pathway in Dermatomyositis: A Possible Mechanism of Perifascicular
Meirong Liu1, Ling Li2, Tingjun Dai3
1From the Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Abstract:
Different mechanisms have been proposed to explain the pathological basis of perifascicular atrophy (PFA), a pathognomonic histologic feature of dermatomyositis (DM); however, the detailed mechanisms remain to be elucidated. There is mitochondrial dysfunction in PFA and expression of mitochondrial apoptosis molecules has been reported in DM. Overexpression of gasdermin E (GSDME) can turn mitochondrial apoptosis to mitochondrial pyroptosis, a newly characterized form of programmed cell death. We determined the expression of proteins involved in the caspase-3- and GSDME-dependent mitochondrial pyroptotic pathway, including BAX, BAK, cytochrome C, caspase-9, caspase-3, GSDME, and IL-1α, in biopsied muscles from DM and control patients. Immunohistochemical analysis showed that those markers were expressed in most fibers in PFA in DM. GSDME-positive and IL-1α-positive staining was mainly localized around punched-out vacuoles or sarcolemma. These markers were significantly upregulated at the protein and mRNA levels in DM versus controls. Our results suggest that caspase-3- and GSDME-dependent mitochondrial pyroptosis are involved in the pathogenetic mechanisms of PFA in DM and that targeting GSDME-dependent mitochondrial pyroptosis may be an effective therapeutic approach for this condition.
Insights
Mitochondrial pyroptosis, a cell death pathway involving gasdermin E (GSDME), is implicated in dermatomyositis-related perifascicular atrophy. Targeting this pathway may offer a new therapeutic strategy for dermatomyositis.
Area of Science:
- Muscle pathology
- Immunology
- Cellular biology
Background:
- Perifascicular atrophy (PFA) is a key feature of dermatomyositis (DM), but its underlying mechanisms are not fully understood.
- Mitochondrial dysfunction and apoptosis are observed in DM, with gasdermin E (GSDME) potentially mediating pyroptosis.
Purpose of the Study:
- To investigate the role of caspase-3 and GSDME-dependent mitochondrial pyroptosis in the pathogenesis of PFA in DM.
- To analyze the expression of key proteins in this pathway in muscle biopsies from DM patients and controls.
Main Methods:
- Immunohistochemical analysis of muscle biopsies from DM patients and healthy controls.
- Quantification of protein and mRNA levels for BAX, BAK, cytochrome C, caspase-9, caspase-3, GSDME, and IL-1α.
Main Results:
- Markers of the caspase-3 and GSDME-dependent mitochondrial pyroptotic pathway were significantly upregulated in DM muscle tissue compared to controls.
- These markers were notably expressed in muscle fibers affected by PFA, with GSDME and IL-1α localized around vacuoles and sarcolemma.
- Both protein and mRNA levels of these pyroptosis markers were elevated in DM patients.
Conclusions:
- Caspase-3 and GSDME-dependent mitochondrial pyroptosis are involved in the development of PFA in dermatomyositis.
- Targeting GSDME-dependent mitochondrial pyroptosis presents a potential therapeutic avenue for treating dermatomyositis.
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