Interleukin 37 Suppresses M1 Macrophage Polarization Through Inhibition of the Notch1 and Nuclear Factor Kappa B Pathways

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.

Current Understanding of IL-37 in Human Health and Disease

“…The imbalance of M1 and M2 macrophage polarization can affect the intensity of the inflammatory responses. Calcific aortic valves present a higher amount of M1 macrophages and less IL-37 expression compared to normal valves (48). RhIL-37 downregulates the expression of inducible nitric oxide synthase, CD11c, IL-6, and monocyte chemoattractant protein 1 (MCP-1) in M1 macrophage in vitro, and inhibits their polarization through the suppression of the activation of the Notch1 and NF-kB pathways (48).…”

The Crosstalk Between Tumor-Associated Macrophages (TAMs) and Tumor Cells and the Corresponding Targeted Therapy

“…In addition, IL-37 can also inhibit the Notch signaling pathway. In fact, IL-37 inhibits M1 macrophage polarization by suppressing the Notch1 and NK-kB pathways (74). However, it has been found that IL-37 is almost not expressed in non-small cell lung cancer tissues, but is highly expressed in adjacent normal tissues (75).…”

Lipoarabinomannan as a Point-of-Care Assay for Diagnosis of Tuberculosis: How Far Are We to Use It?

“…In vivo and in vitro models have demonstrated that low LAM concentration can induce a negative regulation of the activation of the immune system (Driss et al, 2012;Chávez-Galán et al, 2015;Yuan et al, 2019). Perhaps this is because LAM possess multiple epitopes, and these interact with cell surface receptors in different grades of affinity (Choudhary et al, 2018;De et al, 2020;Zhou et al, 2020).…”

“…Recently, it has been described that IL-37 suppresses activation, proliferation, and cytokine production through down-regulation of nuclear factor-kappa B (NF-κB), and that it inhibits macrophage polarization into the M1 subtype (Zhou et al, 2020). However, this immunomodulatory effect is not observed in A TB patients, who have high circulating levels of IL-37 but not a high expression of its receptors IL-18R and IL-1Ra; this is probably a regulatory mechanism exclusive of the alveolar region (Wawrocki et al, 2019;Moideen et al, 2020;Zhang et al, 2020).…”