A sophisticated transcriptional network controlled by several transcription factors enables macrophages to respond and adapt to their surrounding environment. One such transcription factor, Fos-related antigen 1 (FRA1), promotes a pro-inflammatory status in macrophages and impedes the resolution of arthritis in mice, according to results of a new study.
FRA1 has a known function in regulating cytokine expression in macrophages. “As macrophages have pro-inflammatory and destructive potential during rheumatoid arthritis (RA), we wondered if FRA1 could alter the responses of macrophages and the outcome of inflammation and bone and cartilage degeneration during arthritis,” explains Nicole Hannemann, first author of the study.
The researchers investigated the effect of macrophage-specific deletion of FRA1 in the K/BxN serum-induced mouse model of arthritis. Compared with wild-type mice, the FRA1-deficient mice had less severe arthritis, including reduced immune cell infiltration and bone erosion.
In vitro analysis revealed that FRA1 inhibits the expression of the enzyme arginase 1 (ARG1). Indeed, the activity of ARG1 was increased in FRA1-deficient mice compared with wild-type mice. ARG1 catalyses the conversion of L-arginine to L-ornithine and has known immunoregulatory functions.
Treatment of FRA1-deficient mice with an arginase inhibitor increased the severity of arthritis to the extent present in wild-type mice.
Given these findings, the authors investigated the effect of increasing arginase activity through L-arginine supplementation either at arthritis onset or at the peak of inflammation. “We were excited to see that both approaches reduced inflammation and bone degeneration,” says Hannemann.
FRA1-deficient mice had less severe arthritis
“These results are promising and might provide therapeutic opportunities for altering macrophage responses from a pro-inflammatory to a pro-resolving state, which could induce the resolution of inflammation in RA but also in other inflammatory disease,” concludes Hannemann.
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Original article
Hannemann, N. et al. Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis. J. Clin. Invest. https://doi.org/10.1172/JCI96832 (2019)
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McHugh, J. FRA1 in macrophages promotes arthritis. Nat Rev Rheumatol 15, 320 (2019). https://doi.org/10.1038/s41584-019-0233-7
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DOI: https://doi.org/10.1038/s41584-019-0233-7