Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

Abstract

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 Tfr2 fl/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.

Details

Original languageEnglish
Article number102616
JournalRedox biology
Volume60
Publication statusPublished - Apr 2023
Peer-reviewedYes

External IDs

PubMed 36746004

Keywords

Research priority areas of TU Dresden

DFG Classification of Subject Areas according to Review Boards

Subject groups, research areas, subject areas according to Destatis

Sustainable Development Goals

Keywords

  • Humans, Mice, Male, Female, Animals, Mice, Knockout, Iron/metabolism, Iron Overload/pathology, Macrophages/metabolism, Arthritis/metabolism, Receptors, Transferrin/genetics