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Association of Increased F4/80high Macrophages With Suppression of Serum-Transfer Arthritis in Mice With Reduced FLIP in Myeloid Cells.

ABSTRACT: OBJECTIVE:Macrophages are critical in the pathogenesis of rheumatoid arthritis (RA). We recently demonstrated that FLIP is necessary for the differentiation and/or survival of macrophages. We also showed that FLIP is highly expressed in RA synovial macrophages. This study was undertaken to determine if a reduction in FLIP in mouse macrophages reduces synovial tissue macrophages and ameliorates serum-transfer arthritis. METHODS:Mice with Flip deleted in myeloid cells (Flipf/f LysMc/+ mice) and littermate controls were used. Arthritis was induced by intraperitoneal injection of K/BxN serum. Disease severity was evaluated by clinical score and change in ankle thickness, and joints were examined by histology and immunohistochemistry. Cells were isolated from the ankles and bone marrow of the mice and examined by flow cytometry, real-time quantitative reverse transcriptase-polymerase chain reaction, or Western blotting. RESULTS:In contrast to expectations, Flipf/f LysMc/+ mice developed more severe arthritis early in the clinical course, but peak arthritis was attenuated and the resolution phase more complete than in control mice. Prior to the induction of serum-transfer arthritis, the number of tissue-resident macrophages was reduced. On day 9 after arthritis induction, the number of F4/80high macrophages in the joints of the Flipf/f LysMc/+ mice was not decreased, but increased. FLIP was reduced in the F4/80high macrophages in the ankles of the Flipf/f LysMc/+ mice, while F4/80high macrophages expressed an antiinflammatory phenotype in both the Flipf/f LysMc/+ and control mice. CONCLUSION:Our observations suggest that reducing FLIP in macrophages by increasing the number of antiinflammatory macrophages may be an effective therapeutic approach to suppress inflammation, depending on the disease stage.

SUBMITTER: Huang QQ

PROVIDER: S-EPMC5575965 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Association of Increased F4/80<sup>high</sup> Macrophages With Suppression of Serum-Transfer Arthritis in Mice With Reduced FLIP in Myeloid Cells.

Huang Qi-Quan QQ Birkett Robert R Doyle Renee E RE Haines G Kenneth GK Perlman Harris H Shi Bo B Homan Philip P Xing Lianping L Pope Richard M RM

Arthritis & rheumatology (Hoboken, N.J.) 20170801 9

<h4>Objective</h4>Macrophages are critical in the pathogenesis of rheumatoid arthritis (RA). We recently demonstrated that FLIP is necessary for the differentiation and/or survival of macrophages. We also showed that FLIP is highly expressed in RA synovial macrophages. This study was undertaken to determine if a reduction in FLIP in mouse macrophages reduces synovial tissue macrophages and ameliorates serum-transfer arthritis.<h4>Methods</h4>Mice with Flip deleted in myeloid cells (Flip<sup>f/f< ...[more]

PMID: 28511285

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Project description:Key Points Long-term effects of cisplatin are understudied. This study is the first to examine the role of macrophages in cisplatin-induced fibrosis. Depletion of kidney-resident macrophages ameliorated cisplatin-induced fibrosis, whereas depletion of infiltrating macrophages had no effect. This study highlights a pathogenic role for kidney-resident M2 macrophages in the development of fibrosis with repeated nephrotoxic injury. Visual Abstract Background Cisplatin-induced kidney injury remains a major obstacle in utilizing cisplatin as a chemotherapeutic for solid-organ cancers. Thirty percent of patients treated with cisplatin develop acute kidney injury (AKI), and even patients who do not develop AKI are at risk for long-term declines in kidney function and development of chronic kidney disease (CKD). Modeling cisplatin-induced kidney injury in mice has revealed that repeated low doses of cisplatin lead to development of kidney fibrosis. This model can be used to examine AKI-to-CKD transition processes. Macrophages play a role in some of these processes, including immune response, wound healing, and tissue remodeling. Depleting macrophage populations in the kidney reduced fibrosis development in other models of renal fibrosis. Methods We used either C57BL/6 mice with a Ccr2 genetic knockout or liposome encapsulated clodronate (Clodrosome) to deplete macrophage populations during repeated 9 mg/kg cisplatin treatments. We assessed how immune cell populations were altered in the blood and kidney of these mice and how these alterations affected development of renal fibrosis and kidney injury. Results We found that Clodrosome treatment decreased collagen deposition, myofibroblast accumulation, and inflammatory cytokine production, whereas Ccr2 genetic knockout had no effect on these markers after cisplatin treatment. Additionally, Ccr2−/− mice had decreased levels of F4/80lo infiltrating macrophages in the kidney after cisplatin treatments, but Clodrosome treatment depleted F4/80hi resident and CD206+ M2 macrophages. Conclusions These data suggest that Clodrosome depletion of F4/80hi and M2 macrophages in the kidney attenuates development of renal fibrosis after repeated low doses of cisplatin.

Dataset Information

Association of Increased F4/80high Macrophages With Suppression of Serum-Transfer Arthritis in Mice With Reduced FLIP in Myeloid Cells.

Publications

Association of Increased F4/80<sup>high</sup> Macrophages With Suppression of Serum-Transfer Arthritis in Mice With Reduced FLIP in Myeloid Cells.

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