Dataset Information

Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis.

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.

SUBMITTER: Ledesma-Colunga MG

PROVIDER: S-EPMC9932570 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis.

Ledesma-Colunga Maria G MG Baschant Ulrike U Weidner Heike H Alves Tiago C TC Mirtschink Peter P Hofbauer Lorenz C LC Rauner Martina M Rauner Martina M

Redox biology 20230201

<h4>Objective</h4>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.<h4>Methods</h4>Using a global and conditional genetic d ...[more]

PMID: 36746004

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Project description:Rationale: Stroke is a leading causes of human death worldwide. Ischemic damage induces the sterile neuroinflammation, which directly determines the recovery of patients. Lipids, a major component of the brain, significantly altered after stroke. Cholesterol sulfate, a naturally occurring analog of cholesterol, can directly regulate immune cell activation, indicating the possible involvement of cholesterol metabolites in neuroinflammation. Sulfotransferase family 2b member 1 (Sult2b1) is the key enzyme that catalyzes the synthesis of cholesterol sulfate. This study aimed to investigate the function of Sult2b1 and cholesterol sulfate in the neuroinflammation after ischemic stroke. Methods and Results: Sult2b1 -/- and wild-type mice were subjected to transient middle cerebral artery occlusion. Our data showed that Sult2b1 -/- mice had larger infarction and worse neurological scores. To determine whether immune cells were involved in the worsening stroke outcome in Sult2b1 -/- mice, bone marrow transplantation, immune cell depletion, and adoptive monocyte transfer were performed. Combined with CyTOF and immunofluorescence techniques, we demonstrated that after stroke, the peripheral monocyte-derived macrophages were the dominant cell type promoting the pro-inflammatory status in Sult2b1 -/-mice. Using primary bone marrow-derived macrophages, we showed that cholesterol sulfate could attenuate the pro-inflammatory polarization of macrophages under both normal and oxygen-glucose deprivation conditions by regulating the levels of nicotinamide adenine dinucleotide phosphate (NADPH), reactive oxygen species (ROS), and activating the AMP-activated protein kinase (AMPK) - cAMP responsive element-binding protein (CREB) signaling pathway. Conclusions: Sult2b1 -/- promoted the polarization of macrophages into pro-inflammatory status. This trend could be attenuated by adding cholesterol sulfate, which promotes the polarization of macrophages into anti-inflammatory status by metabolic regulation. In this study, we established an inflammation-metabolism axis during the macrophage polarization after ischemic stroke.

Dataset Information

Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis.

Objective

Methods

Results

Conclusion

Publications

Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis.

Similar Datasets

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