Omentin-1 modulates interleukin expression and macrophage polarization: Implications for rheumatoid arthritis therapy.

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Rheumatoid arthritis (RA) is a systemic inflammatory and autoimmune disorder in which monocytes/macrophage infiltrate synovial membrane, differentiating into the pro- and anti-inflammatory M1 and M2 macrophage phenotypes. Omentin-1 is one of the adipokines that has anti-inflammatory and immunomodulatory effects; nevertheless, investigators have yet to elucidate the function of omentin-1 in RA development. It is still unclear how omentin-1 affects human autoimmune disease and what its beneficial role is. Thus, we show that omentin-1 exhibits a therapeutic effect on RA. Utilizing patient or animal tissue, MH7A cell-line, ELISA, and qPCR, we examined the expression of omentin-1 and inflammatory cytokines in the GEO databases. Omentin-1's effects on macrophage polarization were investigated using Immunofluorescence staining (IF) and qPCR. Additionally, the method by which omentin-1 regulates interleukins was discovered by IF labeling for STAT6 translocation, siRNA transfection, IPA software using several and pharmacological inhibitors. Omentin-1's effects were examined in an in vivo investigation using the type II collagen-induced arthritis model, micro-CT, and histological evaluation. Results from the GSE97779 dataset and patients' tissues discovered that the level of omentin-1 and M2 macrophage markers are downregulated in human RA tissue samples compared to healthy tissue and negatively correlated with the expression of pro-inflammatory interleukins (ILs) and M1 macrophage. Stimulation of RA synovial fibroblasts with omentin-1 augmented IL-4 synthesis and subsequently enhanced anti-inflammatory ability as well as M2 polarization. The STAT6 transactivation through AMPK, PI3K, ERK, and JAK cascades regulates omentin-1-induced promotion of IL-4. Importantly, intra-articular injection of omentin-1 blocked collagen-induced arthritis-augmented pro-inflammatory response, cartilage degradation, and bone loss through upregulating IL-4 and M2 macrophages in vivo. Our findings support a potential therapy goal for RA and a tenable mechanism to explain the relationship between omentin-1.