AUTHOR=Mukai Manabu , Uchida Kentaro , Okubo Tadashi , Takano Shotaro , Matsumoto Toshihide , Satoh Masashi , Inoue Gen , Takaso Masashi 

TITLE=Regulation of Tumor Necrosis Factor-α by Peptide Lv in Bone Marrow Macrophages and Synovium

JOURNAL=Frontiers in Medicine

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2021.702126

DOI=10.3389/fmed.2021.702126

ISSN=2296-858X

ABSTRACT=<p><bold>Background:</bold> Bone marrow-derived monocytes/macrophages are recruited into synovial tissue, where they contribute to synovial inflammation in osteoarthritis through inflammatory cytokine production. Recent studies have suggested that V-Set and transmembrane domain-containing 4 (VSTM4) and its fragment, peptide Lv, exhibit immunosuppressive activity on T cells and vascular endothelial growth factor (VEGF)-like activity, respectively. Given that evidence suggests that VEGF may play a role in macrophage function, we investigated peptide Lv-mediated regulation of inflammatory cytokines in bone marrow macrophages (BMMs) and synovial inflammation.</p><p><bold>Method:</bold> To investigate the effects of peptide Lv, BMMs were stimulated with vehicle, LPS, or LPS + peptide Lv, and <italic>Tnfa, Il1b, Il6</italic>, and <italic>Ifng</italic> expression were evaluated using quantitative PCR (qPCR). TNF-α and IFN-γ production was measured using ELISA. To examine the effect of peptide Lv deficiency on macrophages and synovitis, <italic>peptide Lv</italic>-deficient mice were generated using genome editing. LPS-induced <italic>Tnfa</italic> and <italic>Ifng</italic> expression and TNF-α and IFN-γ production were evaluated in BMM isolated from wild-type and <italic>peptide Lv</italic>-deficient mice. Additionally, <italic>Tnfa</italic> and <italic>Ifng</italic> expression levels were compared between wild-type and <italic>peptide Lv</italic>-deficient mice before and after knee injury.</p><p><bold>Results:</bold> Peptide Lv suppressed the LPS-mediated elevation in TNF-α and IFN-γ. LPS stimulation significantly increased TNF-α and IFN-γ production in BMM derived from <italic>peptide Lv</italic>-deficient mice compared to wild-type mice. Synovial TNF-α expression in the injured knee was elevated in <italic>peptide Lv</italic>-deficient compared to wild-type mice.</p><p><bold>Conclusion:</bold> Peptide Lv suppressed TNF-α in macrophages and plays a role in synovial inflammation. Thus, peptide Lv may be a useful therapeutic target for synovitis.</p>