Reprogramming of synovial macrophage metabolism by synovial fibroblasts under inflammatory conditions
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RESEARCH
Reprogramming of synovial macrophage metabolism by synovial fibroblasts under inflammatory conditions Noritaka Saeki1,2* and Yuuki Imai1,2,3*
Abstract Background: Macrophages adapt to microenvironments, and change metabolic status and functions to regulate inflammation and/or maintain homeostasis. In joint cavities, synovial macrophages (SM) and synovial fibroblasts (SF) maintain homeostasis. However, under inflammatory conditions such as rheumatoid arthritis (RA), crosstalk between SM and SF remains largely unclear. Methods: Immunofluorescent staining was performed to identify localization of SM and SF in synovium of collagen antibody induced arthritis (CAIA) model mice and normal mice. Murine arthritis tissue-derived SM (ADSM), arthritis tissue-derived SF (ADSF) and normal tissue-derived SF (NDSF) were isolated and the purity of isolated cells was examined by RT-qPCR and flow cytometry analysis. RNA-seq was conducted to reveal gene expression profile in ADSM, NDSF and ADSF. Cellular metabolic status and expression levels of metabolic genes and inflammatory genes were analyzed in ADSM treated with ADSM-conditioned medium (ADSM-CM), NDSF-CM and ADSF-CM. Results: SM and SF were dispersed in murine hyperplastic synovium. Isolations of ADSM, NDSF and ADSF to analyze the crosstalk were successful with high purity. From gene expression profiles by RNA-seq, we focused on secretory factors in ADSF-CM, which can affect metabolism and inflammatory activity of ADSM. ADSM exposed to ADSF-CM showed significantly upregulated glycolysis and mitochondrial respiration as well as glucose and glutamine uptake relative to ADSM exposed to ADSM-CM and NDSF-CM. Furthermore, mRNA expression levels of metabolic genes, such as Slc2a1, Slc1a5, CD36, Pfkfb1, Pfkfb3 and Irg1, were significantly upregulated in ADSM treated with ADSF-CM. Inflammation marker genes, including Nos2, Tnf, Il-1b and CD86, and the anti-inflammatory marker gene, Il-10, were also substantially upregulated by ADSF-CM. On the other hand, NDSF-CM did not affect metabolism and gene expression in ADSM. Conclusions: These findings suggest that crosstalk between SM and SF under inflammatory conditions can induce metabolic reprogramming and extend SM viability that together can contribute to chronic inflammation in RA. Keywords: Rheumatoid arthritis, Synovial macrophage, Synovial fibroblast, Metabolic reprogramming, Chronic inflammation
*Correspondence: [email protected]‑u.ac.jp; y‑[email protected]‑u.ac.jp 1 Division of Laboratory Animal Research, Advanced Research Support Center, Ehime University, Shitsukawa, Toon, Ehime 791‑0295, Japan Full list of author information is available at the end of the article
Background Inflammation is a biological defense system to maintain homeostasis, but excessive inflammation such as that present in autoimmune diseases like rheumatoid arthritis (RA) induces onset and progression of pathological status. Among immune cells, macrophages are heterogenous and play multiple roles in several tissues
© The Author(s) 2020. Op
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