Kallistatin Inhibits Atherosclerotic Inflammation by Regulating Macrophage Polarization

Abstract

Kallistatin (KS) has been recognized as a plasma protein with anti-inflammatory functions. Macrophages are the primary inflammatory cells in atherosclerotic plaques. However, it is unknown whether KS plays a role in macrophage development and the pathogenesis of atherosclerosis. This study investigated the role of KS in macrophage development, a key pathological process in atherosclerosis. An atherosclerosis model was established in ApoE mice via partial left carotid artery (PLCA) ligation. An adenovirus vector (Ad. HKS) containing the human KS gene was delivered via the tail vein before PLCA ligation. The mice were divided into two groups: the PLCA + Ad. HKS and PLCA + adenovirus vector (Ad. Null) groups and followed for 2 and 4 weeks. Human KS was expressed in the mice after KS gene delivery. In addition, KS significantly inhibited plaque formation and reduced inflammation in the plaques and liver 4 weeks after gene delivery. Moreover, KS gene delivery significantly increased the expression of interleukin-10 and Arginase 1, which are M2 macrophage markers, and reduced the expression of inducible nitric oxide synthase and monocyte chemotactic protein 1, which are M1 macrophage markers. Furthermore, in cultured RAW 264.7 macrophages, KS significantly stimulated M2 marker expression and differentiation and decreased M1 marker expression, as determined by flow cytometry and real-time polymerase chain reaction. These effects were blocked by Krüppel-like factor 4 small-interfering RNA oligonucleotides. These findings demonstrate that KS inhibits atherosclerotic plaque formation and regulates M1/M2 macrophage polarization via Krüppel-like factor 4 activation.

<p>HSPA12B Secreted by Tumor-Associated Endothelial Cells Might Induce M2 Polarization of Macrophages via Activating PI3K/Akt/mTOR Signaling</p>

“…RAW 264.7 cells are a macrophage-like cell line that has been widely used to study macrophage polarization. 18 , 19 RAW264.7 cells were cultured in high-glucose Dulbecco’s Modification of Eagle’s Medium (DMEM) (HyClone, Logan, UT, USA) with 10% fetal bovine serum (FBS) and 100 U/mL penicillin, and 100 μg/mL streptomycin (Clark Bioscience, Seabrook, MD, USA). PTECs and HUVECs were cultured in endothelial cell medium (ECM, Sciencell, San Diego, CA, USA) supplemented with 5% FBS, 1% endothelial cell growth supplements (ECGS), 100 U/mL penicillin, and 100 μg/mL streptomycin.…”

Macrophage Plasticity and Atherosclerosis Therapy

“…Functional HDL particles can suppress inflammation by activating ATF3 and STAT6, which promotes macrophage migration and reverses M1-polarized macrophages to an M2 phenotype (Sanson et al, 2013;Sha et al, 2017). Kallistatin, a plasma protein with anti-inflammatory effect, can inhibit macrophage polarization toward M1 phenotype and promote M2 macrophage polarization via KLF4 activation (Li et al, 2019). IL-19 or recombinant IL-19 induces a reduction in macrophage number and atherosclerotic plaque and an enrichment in M2 macrophages via activating STATs, KLF4, and PPARγ in mice (Gabunia et al, 2016).…”

Identification of hepatitis B virus and liver cancer bridge molecules based on functional module network

“…FOS signal transduction is associated with TLR9-mediated IFN production in plasma-like dendritic cells, and the gene expression level of it is also significantly changed in HCC[38,39]. KLF4 affects inflammation by regulating M1/M2 macrophage polarization, and can also be used as a candidate marker for HCC development[40,41]. The regulation of small RNA is the focus of biological mechanism research.…”