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ANGPTL2 Induces Synovial Inflammation via LILRB2

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Abstract

Angiopoietin-like proteins (ANGPTLs) are circulating proteins that are expressed in various cells and tissues and are thought to be involved in the repair and remodeling of damaged tissues; however, ANGPTL2 hyperfunction has been shown to cause chronic inflammation, leading to the progression of various diseases. ANGPTL2 is known to exert cellular effects via receptors such as integrin α5β1 and leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2); however, their roles in ANGPTL2-induced inflammation remain unclear. In this study, we investigated the mechanisms underlying ANGPTL2-induced inflammation involving LILRB2 and various signaling pathways in human fibroblast-like synoviocytes (HFLS). The effects of ANGPTL2 and an anti-LILRB2 antibody on the gene expression of various inflammation-related factors were examined using real-time RT-PCR, while their effects on MAPK, NF-κB, and Akt phosphorylation were analyzed by western blotting. We found that the addition of ANGPTL2 enhanced the gene expression of inflammatory factors, whereas pretreatment with the anti-LILRB2 antibody for 12 h decreased the expression of these factors. Similarly, ANGPTL2 addition activated the phosphorylation of ERK, p38, JNK, NF-κB, and Akt in HFLS; however, this effect was significantly inhibited by pretreatment with the anti-LILRB2 antibody. Together, the findings of this study demonstrate that ANGPTL2 induces the expression of inflammatory factors via LILRB2 in synovial cells. Therefore, LILRB2 could be a potential therapeutic agent for treating matrix degradation in osteoarthritis.

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Acknowledgements

We would like to thank all members of the Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical and Health Sciencess for their support of the present study.

Funding

This study was funded by Grants-in-Aid (No. 18H0631000) for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

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Authors and Affiliations

  1. Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical and Health Sciences, Kasumi 1-2-3, Minami-ku, Hiroshima-shi, Hiroshima Prefecture, Japan

    Sayuri Nishiyama, Naoto Hirose, Makoto Yanoshita, Mami Takano, Naoki Kubo, Yuka Yamauchi, Azusa Onishi, Shota Ito, Shuzo Sakata, Daiki Kita, Yuki Asakawa-Tanne & Kotaro Tanimoto

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  1. Sayuri Nishiyama
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  2. Naoto Hirose
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Contributions

Sayuri Nishiyama: data curation; formal analysis; investigation; visualization; writing-original draft. Naoto Hirose: conceptualization; methodology; project administration; supervision; writing-review and editing. Makoto Yanoshita: investigation. Mami Takano: investigation. Naoki Kubo: investigation. Yuka Yamauchi: investigation. Azusa Onishi: investigation. Shota Ito: investigation. Shuzo Sakata: investigation. Daiki Kita: investigation. Yuki Asakawa-Tanne: data curation. Kotaro Tanimoto: conceptualization; project administration; supervision; writing-review and editing.

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Correspondence to Naoto Hirose.

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Nishiyama, S., Hirose, N., Yanoshita, M. et al. ANGPTL2 Induces Synovial Inflammation via LILRB2. Inflammation 44, 1108–1118 (2021). https://doi.org/10.1007/s10753-020-01406-7

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