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Exp. Mol. Med., 01 April 2024 | https://doi.org/10.1038/s12276-024-01188-0 The acute phase reactant orosomucoid-2 directly promotes rheumatoid inflammation

Ki-Myo Kim ^1,2,5, Kang-Gu Lee ^1,2,5, Saseong Lee ^1,5, Bong-Ki Hong ¹, Heejae Yun ^1,2, Yune-Jung Park ^1,3, Seung-Ah Yoo ^1,2,* and Wan-Uk Kim ^1,4,*

¹Center for Integrative Rheumatoid Transcriptomics and Dynamics, The Catholic University of Korea, Seoul, South Korea.
²Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
³Division of Rheumatology, Department of Internal Medicine, St. Vincent’s Hospital, The Catholic University of Korea, Suwon, South Korea.
⁴Department of Internal Medicine, The Catholic University of Korea, Seoul, South Korea.
⁵These authors contributed equally: Ki-Myo Kim, Kang-Gu Lee, Saseong Lee.

^*Corresponding authors: correspondence to Seung-Ah Yoo or Wan-Uk Kim

Abstract

Acute phase proteins involved in chronic inflammatory diseases have not been systematically analyzed. Here, global proteome profiling of serum and urine revealed that orosomucoid-2 (ORM2), an acute phase reactant, was differentially expressed in rheumatoid arthritis (RA) patients and showed the highest fold change. Therefore, we questioned the extent to which ORM2, which is produced mainly in the liver, actively participates in rheumatoid inflammation. Surprisingly, ORM2 expression was upregulated in the synovial fluids and synovial membranes of RA patients. The major cell types producing ORM2 were synovial macrophages and fibroblast-like synoviocytes (FLSs) from RA patients. Recombinant ORM2 robustly increased IL-6, TNF-α, CXCL8 (IL-8), and CCL2 production by RA macrophages and FLSs via the NF-κB and p38 MAPK pathways. Interestingly, glycophorin C, a membrane protein for determining erythrocyte shape, was the receptor for ORM2. Intra-articular injection of ORM2 increased the severity of arthritis in mice and accelerated the infiltration of macrophages into the affected joints. Moreover, circulating ORM2 levels correlated with RA activity and radiographic progression. In conclusion, the acute phase protein ORM2 can directly increase the production of proinflammatory mediators and promote chronic arthritis in mice, suggesting that ORM2 could be a new therapeutic target for RA.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-12)
연구진국내 연구진
분야 의약학 > 면역의학

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