Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis
Abstract The TAM tyrosine kinases, Axl and MerTK, play an important role in rheumatoid arthritis (RA). Here, using a unique synovial tissue bioresource of patients with RA matched for disease stage and treatment exposure, we assessed how Axl and MerTK relate to synovial histopathology and disease ac...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46564-6 |
| _version_ | 1797259141474942976 |
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| author | Alessandra Nerviani Marie-Astrid Boutet Giulia Maria Ghirardi Katriona Goldmann Elisabetta Sciacca Felice Rivellese Elena Pontarini Edoardo Prediletto Federico Abatecola Mattia Caliste Sara Pagani Daniele Mauro Mattia Bellan Cankut Cubuk Rachel Lau Sarah E. Church Briana M. Hudson Frances Humby Michele Bombardieri Myles J. Lewis Costantino Pitzalis |
| author_facet | Alessandra Nerviani Marie-Astrid Boutet Giulia Maria Ghirardi Katriona Goldmann Elisabetta Sciacca Felice Rivellese Elena Pontarini Edoardo Prediletto Federico Abatecola Mattia Caliste Sara Pagani Daniele Mauro Mattia Bellan Cankut Cubuk Rachel Lau Sarah E. Church Briana M. Hudson Frances Humby Michele Bombardieri Myles J. Lewis Costantino Pitzalis |
| author_sort | Alessandra Nerviani |
| collection | DOAJ |
| description | Abstract The TAM tyrosine kinases, Axl and MerTK, play an important role in rheumatoid arthritis (RA). Here, using a unique synovial tissue bioresource of patients with RA matched for disease stage and treatment exposure, we assessed how Axl and MerTK relate to synovial histopathology and disease activity, and their topographical expression and longitudinal modulation by targeted treatments. We show that in treatment-naive patients, high AXL levels are associated with pauci-immune histology and low disease activity and inversely correlate with the expression levels of pro-inflammatory genes. We define the location of Axl/MerTK in rheumatoid synovium using immunohistochemistry/fluorescence and digital spatial profiling and show that Axl is preferentially expressed in the lining layer. Moreover, its ectodomain, released in the synovial fluid, is associated with synovial histopathology. We also show that Toll-like-receptor 4-stimulated synovial fibroblasts from patients with RA modulate MerTK shedding by macrophages. Lastly, Axl/MerTK synovial expression is influenced by disease stage and therapeutic intervention, notably by IL-6 inhibition. These findings suggest that Axl/MerTK are a dynamic axis modulated by synovial cellular features, disease stage and treatment. |
| first_indexed | 2024-04-24T23:04:43Z |
| format | Article |
| id | doaj.art-479b8ed47d1c4eb09e9de80de7cc33ef |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T23:04:43Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-479b8ed47d1c4eb09e9de80de7cc33ef2024-03-17T12:31:25ZengNature PortfolioNature Communications2041-17232024-03-0115111610.1038/s41467-024-46564-6Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritisAlessandra Nerviani0Marie-Astrid Boutet1Giulia Maria Ghirardi2Katriona Goldmann3Elisabetta Sciacca4Felice Rivellese5Elena Pontarini6Edoardo Prediletto7Federico Abatecola8Mattia Caliste9Sara Pagani10Daniele Mauro11Mattia Bellan12Cankut Cubuk13Rachel Lau14Sarah E. Church15Briana M. Hudson16Frances Humby17Michele Bombardieri18Myles J. Lewis19Costantino Pitzalis20Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustNanoString Technologies IncNanoString Technologies IncCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustCentre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London & NIHR BRC Barts Health NHS TrustAbstract The TAM tyrosine kinases, Axl and MerTK, play an important role in rheumatoid arthritis (RA). Here, using a unique synovial tissue bioresource of patients with RA matched for disease stage and treatment exposure, we assessed how Axl and MerTK relate to synovial histopathology and disease activity, and their topographical expression and longitudinal modulation by targeted treatments. We show that in treatment-naive patients, high AXL levels are associated with pauci-immune histology and low disease activity and inversely correlate with the expression levels of pro-inflammatory genes. We define the location of Axl/MerTK in rheumatoid synovium using immunohistochemistry/fluorescence and digital spatial profiling and show that Axl is preferentially expressed in the lining layer. Moreover, its ectodomain, released in the synovial fluid, is associated with synovial histopathology. We also show that Toll-like-receptor 4-stimulated synovial fibroblasts from patients with RA modulate MerTK shedding by macrophages. Lastly, Axl/MerTK synovial expression is influenced by disease stage and therapeutic intervention, notably by IL-6 inhibition. These findings suggest that Axl/MerTK are a dynamic axis modulated by synovial cellular features, disease stage and treatment.https://doi.org/10.1038/s41467-024-46564-6 |
| spellingShingle | Alessandra Nerviani Marie-Astrid Boutet Giulia Maria Ghirardi Katriona Goldmann Elisabetta Sciacca Felice Rivellese Elena Pontarini Edoardo Prediletto Federico Abatecola Mattia Caliste Sara Pagani Daniele Mauro Mattia Bellan Cankut Cubuk Rachel Lau Sarah E. Church Briana M. Hudson Frances Humby Michele Bombardieri Myles J. Lewis Costantino Pitzalis Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis Nature Communications |
| title | Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis |
| title_full | Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis |
| title_fullStr | Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis |
| title_full_unstemmed | Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis |
| title_short | Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis |
| title_sort | axl and mertk regulate synovial inflammation and are modulated by il 6 inhibition in rheumatoid arthritis |
| url | https://doi.org/10.1038/s41467-024-46564-6 |
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