Abstract
Macrophage-orchestrated chronic inflammation plays an important role in cardiovascular disease, including accelerating the development of calcific aortic valve disease (CAVD). M1 and M2 macrophage polarization imbalances can alter intensity of inflammatory responses. Recombinant human interleukin 37 (IL-37) could be involved in regulating immune cell function to attenuate inflammation. This study aimed to identify IL-37 specifically modulates M1 polarization and investigate the underlying mechanism. Compared with normal valves, there are more M1 macrophages accumulation and less IL-37 expression in calcific aortic valves, which may indicate a negative relationship between IL-37 and M1 polarization. THP-1 cells could differentiate into resting macrophages with phorbol-12-myristate-13-acetate (PMA) and then polarize into M1 macrophages following treatment with lipopolysaccharide (LPS) and interferon gamma (IFN-γ). In vitro, recombinant human IL-37 attenuated the expression of inducible nitric oxide synthase (iNOS), CD11c, IL-6 and monocyte chemoattractant protein 1 (MCP-1) in M1 but augmented the expression of CD206 and IL-10 in M2. The suppression of M1 polarization was associated with the inhibition of the activation of the nuclear factor kappa B (NF-κB) and Notch1 signaling pathways. These results demonstrated that IL-37 inhibits the macrophages polarizing into M1 type via the inhibition of the Notch1 and nuclear factor kappa B pathways. In summary, IL-37 could be a potential therapeutic candidate for progressive CAVD by modulating M1 polarization and its orchestrated inflammation.
Highlights
Calcific aortic valve disease (CAVD) is recognized as a chronic progressive inflammatory disease and has become a leading cause of cardiovascular disease in people aged 65 years or older and the second most common indication for cardiac surgery (Mohler et al, 2001; Rajamannan et al, 2011)
Immunoblots of noncalcified and calcified aortic valve tissues showed the same trend (Supplementary Figure S2B). These findings suggested that interleukin 37 (IL-37) may inhibit M1 but augment M2 infiltration. These results demonstrated that M1 macrophage levels increased in Magnification, 400×, scale bar = 50 μm. (F) CD11c + cell-to-CD206 + cell ratio in CAVD and non-CAVD
We showed that IL-37 attenuated the inflammation induced by M1 macrophages and may convert M1 into M2 macrophages, and had a potential to dampen the calcification of CAVD
Summary
Calcific aortic valve disease (CAVD) is recognized as a chronic progressive inflammatory disease and has become a leading cause of cardiovascular disease in people aged 65 years or older and the second most common indication for cardiac surgery (Mohler et al, 2001; Rajamannan et al, 2011). M1 macrophages can be induced by Toll-like receptor (TLR) ligands and IFN-γ while M2 by IL4/IL13 (M2a), immune complex (M2b), and the anti-inflammatory cytokines IL-10 or transforming growth factor-β (M2c) (Zhou et al, 2014). M1 macrophages express numerous pro-inflammatory cytokines, such as IL-1β, IL-6, IL-23, inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-α), while M2 macrophages secrete molecules including Arginase (Arg1), IL-10 and transforming growth factor-β1 (TGF-β1) which are associated with parasite infestation, tissue remodeling and tumor progression (Sica and Mantovani, 2012; Liu et al, 2014). The finding that M1 macrophages accumulate in aortic valvular lesions suggests that the inflammation induced by M1 macrophages is pivotal in cardiovascular calcification (Li et al, 2016)
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