Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis
Objective: Rheumatoid arthritis is an inflammatory joint disease in which synovial iron deposition has been described. Transferrin receptor 2 (Tfr2) represents a critical regulator of systemic iron levels. Loss of Tfr2 function in humans and mice results in iron overload. As iron contributes to infl...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231723000174 |
| _version_ | 1811172050107105280 |
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| author | Maria G. Ledesma-Colunga Ulrike Baschant Heike Weidner Tiago C. Alves Peter Mirtschink Lorenz C. Hofbauer Martina Rauner |
| author_facet | Maria G. Ledesma-Colunga Ulrike Baschant Heike Weidner Tiago C. Alves Peter Mirtschink Lorenz C. Hofbauer Martina Rauner |
| author_sort | Maria G. Ledesma-Colunga |
| collection | DOAJ |
| description | Objective: Rheumatoid arthritis is an inflammatory joint disease in which synovial iron deposition has been described. Transferrin receptor 2 (Tfr2) represents a critical regulator of systemic iron levels. Loss of Tfr2 function in humans and mice results in iron overload. As iron contributes to inflammatory processes, we investigated whether Tfr2-deletion affects the pathogenesis of inflammatory arthritis in an iron-dependent manner. Methods: Using a global and conditional genetic disruption of Tfr2, we assessed the relevance of Tfr2 in K/BxN serum-transfer arthritis (STA) and macrophage polarization. Results: Male Tfr2−/− mice subjected to STA developed pronounced joint swelling, and bone erosion as compared to Tfr2+/+ littermate-controls (P < 0.01). Furthermore, an increase of neutrophils and macrophages/monocytes was observed in the inflammatory infiltrate within the paws of Tfr2−/− mice. To elucidate whether Tfr2 in myeloid cells has a direct role in the pathogenesis of arthritis or whether the effects were mediated via the systemic iron overload, we induced STA in Tfr2fl/fl-LysMCre + mice, which showed normal iron-loading. Cre + female mice displayed increased disease development compared to Cre-controls. As macrophages regulate iron availability and innate immunity, we hypothesized that Tfr2-deficiency would polarize macrophages toward a pro-inflammatory state (M1) that contributes to arthritis progression. In response to IFN-γ stimulation, Tfr2−/− macrophages showed increased expression of M1-like cytokines, IFN-γ-target genes, nitric-oxide production, and prolonged STAT1 activation compared to Tfr2+/+ macrophages (P < 0.01), while pre-treatment with ruxolitinib abolished Tfr2-driven M1-like polarization. Conclusion: Taken together, these findings suggest a protective role of Tfr2 in macrophages on the progression of arthritis via suppression of M1-like polarization. |
| first_indexed | 2024-04-10T17:24:05Z |
| format | Article |
| id | doaj.art-b6dfec1e6fe644efb74ea14a924671ec |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-10T17:24:05Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-b6dfec1e6fe644efb74ea14a924671ec2023-02-05T04:16:10ZengElsevierRedox Biology2213-23172023-04-0160102616Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritisMaria G. Ledesma-Colunga0Ulrike Baschant1Heike Weidner2Tiago C. Alves3Peter Mirtschink4Lorenz C. Hofbauer5Martina Rauner6Department of Medicine III and Center for Healthy Aging, Technische Universität Dresden, Dresden, GermanyDepartment of Medicine III and Center for Healthy Aging, Technische Universität Dresden, Dresden, GermanyDepartment of Medicine III and Center for Healthy Aging, Technische Universität Dresden, Dresden, GermanyInstitute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, GermanyInstitute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, GermanyDepartment of Medicine III and Center for Healthy Aging, Technische Universität Dresden, Dresden, GermanyDepartment of Medicine III and Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany; Corresponding author. Division of Molecular Bone Biology, Department of Medicine III, Technische Universität Dresden, 01307, Dresden, Germany.Objective: Rheumatoid arthritis is an inflammatory joint disease in which synovial iron deposition has been described. Transferrin receptor 2 (Tfr2) represents a critical regulator of systemic iron levels. Loss of Tfr2 function in humans and mice results in iron overload. As iron contributes to inflammatory processes, we investigated whether Tfr2-deletion affects the pathogenesis of inflammatory arthritis in an iron-dependent manner. Methods: Using a global and conditional genetic disruption of Tfr2, we assessed the relevance of Tfr2 in K/BxN serum-transfer arthritis (STA) and macrophage polarization. Results: Male Tfr2−/− mice subjected to STA developed pronounced joint swelling, and bone erosion as compared to Tfr2+/+ littermate-controls (P < 0.01). Furthermore, an increase of neutrophils and macrophages/monocytes was observed in the inflammatory infiltrate within the paws of Tfr2−/− mice. To elucidate whether Tfr2 in myeloid cells has a direct role in the pathogenesis of arthritis or whether the effects were mediated via the systemic iron overload, we induced STA in Tfr2fl/fl-LysMCre + mice, which showed normal iron-loading. Cre + female mice displayed increased disease development compared to Cre-controls. As macrophages regulate iron availability and innate immunity, we hypothesized that Tfr2-deficiency would polarize macrophages toward a pro-inflammatory state (M1) that contributes to arthritis progression. In response to IFN-γ stimulation, Tfr2−/− macrophages showed increased expression of M1-like cytokines, IFN-γ-target genes, nitric-oxide production, and prolonged STAT1 activation compared to Tfr2+/+ macrophages (P < 0.01), while pre-treatment with ruxolitinib abolished Tfr2-driven M1-like polarization. Conclusion: Taken together, these findings suggest a protective role of Tfr2 in macrophages on the progression of arthritis via suppression of M1-like polarization.http://www.sciencedirect.com/science/article/pii/S2213231723000174 |
| spellingShingle | Maria G. Ledesma-Colunga Ulrike Baschant Heike Weidner Tiago C. Alves Peter Mirtschink Lorenz C. Hofbauer Martina Rauner Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis Redox Biology |
| title | Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis |
| title_full | Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis |
| title_fullStr | Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis |
| title_full_unstemmed | Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis |
| title_short | Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis |
| title_sort | transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723000174 |
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