The Activation of JAK/STAT3 Signaling and the Complement System Modulate Inflammation in the Primary Human Dermal Fibroblasts of PXE Patients
Previous studies revealed a link between inflammation and overactivation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling in syndromes associated with aging. Pseudoxanthoma elasticum (PXE), a rare autosomal-recessive disorder, arises from mutations in <i...
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MDPI AG
2023-09-01
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| Online Access: | https://www.mdpi.com/2227-9059/11/10/2673 |
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| author | Christopher Lindenkamp Ricarda Plümers Michel R. Osterhage Olivier M. Vanakker Judith Van Wynsberghe Cornelius Knabbe Doris Hendig |
| author_facet | Christopher Lindenkamp Ricarda Plümers Michel R. Osterhage Olivier M. Vanakker Judith Van Wynsberghe Cornelius Knabbe Doris Hendig |
| author_sort | Christopher Lindenkamp |
| collection | DOAJ |
| description | Previous studies revealed a link between inflammation and overactivation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling in syndromes associated with aging. Pseudoxanthoma elasticum (PXE), a rare autosomal-recessive disorder, arises from mutations in <i>ATP-binding cassette subfamily C member 6</i> (<i>ABCC6</i>). On a molecular level, PXE shares similarities with Hutchinson–Gilford progeria syndrome, such as increased activity of senescence-associated- beta-galactosidase or high expression of inflammatory factors. Thus, this study’s aim was the evaluation of activated STAT3 and the influence of JAK1/2-inhibitor baricitinib (BA) on inflammatory processes such as the complement system in PXE. Analysis of activation of STAT3 was performed by immunofluorescence and Western blot, while inflammatory processes and complement system factors were determined based on mRNA expression and protein level. Our results assume overactivation of JAK/STAT3 signaling, increased expression levels of several complement factors and high C3 protein concentration in the sera of PXE patients. Supplementation with BA reduces JAK/STAT3 activation and partly reduces inflammation as well as the gene expression of complement factors belonging to the C1 complex and C3 convertase in PXE fibroblasts. Our results indicate a link between JAK/STAT3 signaling and complement activation contributing to the proinflammatory phenotype in PXE fibroblasts. |
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| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T21:25:19Z |
| publishDate | 2023-09-01 |
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| spelling | doaj.art-44a0ddada541404e99cc3aedeb89eca32023-11-19T15:45:26ZengMDPI AGBiomedicines2227-90592023-09-011110267310.3390/biomedicines11102673The Activation of JAK/STAT3 Signaling and the Complement System Modulate Inflammation in the Primary Human Dermal Fibroblasts of PXE PatientsChristopher Lindenkamp0Ricarda Plümers1Michel R. Osterhage2Olivier M. Vanakker3Judith Van Wynsberghe4Cornelius Knabbe5Doris Hendig6Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, GermanyInstitut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, GermanyInstitut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, GermanyCenter for Medical Genetics, Ghent University Hospital, 9000 Ghent, BelgiumCenter for Medical Genetics, Ghent University Hospital, 9000 Ghent, BelgiumInstitut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, GermanyInstitut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, GermanyPrevious studies revealed a link between inflammation and overactivation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling in syndromes associated with aging. Pseudoxanthoma elasticum (PXE), a rare autosomal-recessive disorder, arises from mutations in <i>ATP-binding cassette subfamily C member 6</i> (<i>ABCC6</i>). On a molecular level, PXE shares similarities with Hutchinson–Gilford progeria syndrome, such as increased activity of senescence-associated- beta-galactosidase or high expression of inflammatory factors. Thus, this study’s aim was the evaluation of activated STAT3 and the influence of JAK1/2-inhibitor baricitinib (BA) on inflammatory processes such as the complement system in PXE. Analysis of activation of STAT3 was performed by immunofluorescence and Western blot, while inflammatory processes and complement system factors were determined based on mRNA expression and protein level. Our results assume overactivation of JAK/STAT3 signaling, increased expression levels of several complement factors and high C3 protein concentration in the sera of PXE patients. Supplementation with BA reduces JAK/STAT3 activation and partly reduces inflammation as well as the gene expression of complement factors belonging to the C1 complex and C3 convertase in PXE fibroblasts. Our results indicate a link between JAK/STAT3 signaling and complement activation contributing to the proinflammatory phenotype in PXE fibroblasts.https://www.mdpi.com/2227-9059/11/10/2673pseudoxanthoma elasticumJAK/STAT3complement systembaricitinib |
| spellingShingle | Christopher Lindenkamp Ricarda Plümers Michel R. Osterhage Olivier M. Vanakker Judith Van Wynsberghe Cornelius Knabbe Doris Hendig The Activation of JAK/STAT3 Signaling and the Complement System Modulate Inflammation in the Primary Human Dermal Fibroblasts of PXE Patients Biomedicines pseudoxanthoma elasticum JAK/STAT3 complement system baricitinib |
| title | The Activation of JAK/STAT3 Signaling and the Complement System Modulate Inflammation in the Primary Human Dermal Fibroblasts of PXE Patients |
| title_full | The Activation of JAK/STAT3 Signaling and the Complement System Modulate Inflammation in the Primary Human Dermal Fibroblasts of PXE Patients |
| title_fullStr | The Activation of JAK/STAT3 Signaling and the Complement System Modulate Inflammation in the Primary Human Dermal Fibroblasts of PXE Patients |
| title_full_unstemmed | The Activation of JAK/STAT3 Signaling and the Complement System Modulate Inflammation in the Primary Human Dermal Fibroblasts of PXE Patients |
| title_short | The Activation of JAK/STAT3 Signaling and the Complement System Modulate Inflammation in the Primary Human Dermal Fibroblasts of PXE Patients |
| title_sort | activation of jak stat3 signaling and the complement system modulate inflammation in the primary human dermal fibroblasts of pxe patients |
| topic | pseudoxanthoma elasticum JAK/STAT3 complement system baricitinib |
| url | https://www.mdpi.com/2227-9059/11/10/2673 |
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