Twist1 Regulates Macrophage Plasticity To Promote Renal Fibrosis Through Galectin-3

2021 ◽  
Author(s):  
Qingfeng Wu ◽  
Shiren Sun ◽  
Lei Wei ◽  
Minna Liu ◽  
Hao Liu ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Interstitial Fibrosis ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Kidney Fibrosis ◽  
Galectin 3 ◽  
M2 Macrophage Polarization ◽  
Macrophage Plasticity ◽  
Stage Renal Disease

Abstract Renal interstitial fibrosis is the pathological basis of end-stage renal disease, in which the heterogeneity of macrophages in renal microenvironment plays an important role. However, the molecular mechanisms of macrophage plasticity during renal fibrosis progression remain unclear. In this study, we found for the first time that increased expression of Twist1 in macrophages was significantly associated with the severity of renal fibrosis in IgA nephropathy patients and mice with unilateral ureteral obstruction (UUO). Ablation of Twist1 in macrophages markedly alleviated renal tubular injury and renal fibrosis in UUO mice, accompanied by a lower extent of macrophage infiltration and M2 polarization in the kidney. The knockdown of Twist1 inhibited the chemotaxis and migration of macrophages, at least partially, through the CCL2/CCR2 axis. Twist1 downregulation inhibited M2 macrophage polarization and reduced the secretion of the profibrotic factors Arg1, MR (CD206), IL-10, and TGF-β. Galectin-3 was decreased in the macrophages of the conditional Twist1-deficient mice, and Twist1 was shown to directly activate galectin-3 transcription. Up-regulation of galectin-3 recovered Twist1-mediated M2 macrophage polarization. In conclusion, Twist1/galectin-3 signaling regulates macrophage plasticity (M2 phenotype) and promotes renal fibrosis. This study could suggest new strategies for delaying kidney fibrosis in patients with chronic kidney disease.

M1- and M2-macrophage polarization in rat liver cirrhosis induced by thioacetamide (TAA), focusing on Iba1 and galectin-3

2014 ◽  
Vol 96 (3) ◽  
pp. 382-392 ◽  
Author(s):  
Kavindra Kumara Wijesundera ◽  
Takeshi Izawa ◽  
Anusha Hemamali Tennakoon ◽  
Hiroshi Murakami ◽  
Hossain M. Golbar ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Rat Liver ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Galectin 3 ◽  
M2 Macrophage Polarization

scholarly journals STAT6 Deficiency Attenuates Myeloid Fibroblast Activation and Macrophage Polarization in Experimental Folic Acid Nephropathy

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3057
Author(s):  
Baihai Jiao ◽  
Changlong An ◽  
Hao Du ◽  
Melanie Tran ◽  
Penghua Wang ◽  
...  
Keyword(s):  
Folic Acid ◽  
Kidney Disease ◽  
Knockout Mice ◽  
Renal Fibrosis ◽  
Matrix Protein ◽  
Macrophage Polarization ◽  
Extracellular Matrix Protein ◽  
M2 Macrophage ◽  
Fibroblast Activation ◽  
M2 Macrophage Polarization

Renal fibrosis is a pathologic feature of chronic kidney disease, which can lead to end-stage kidney disease. Myeloid fibroblasts play a central role in the pathogenesis of renal fibrosis. However, the molecular mechanisms pertaining to myeloid fibroblast activation remain to be elucidated. In the present study, we examine the role of signal transducer and activator of transcription 6 (STAT6) in myeloid fibroblast activation, macrophage polarization, and renal fibrosis development in a mouse model of folic acid nephropathy. STAT6 is activated in the kidney with folic acid nephropathy. Compared with folic-acid-treated wild-type mice, STAT6 knockout mice had markedly reduced myeloid fibroblasts and myofibroblasts in the kidney with folic acid nephropathy. Furthermore, STAT6 knockout mice exhibited significantly less CD206 and PDGFR-β dual-positive fibroblast accumulation and M2 macrophage polarization in the kidney with folic acid nephropathy. Consistent with these findings, STAT6 knockout mice produced less extracellular matrix protein, exhibited less severe interstitial fibrosis, and preserved kidney function in folic acid nephropathy. Taken together, these results have shown that STAT6 plays a critical role in myeloid fibroblasts activation, M2 macrophage polarization, extracellular matrix protein production, and renal fibrosis development in folic acid nephropathy. Therefore, targeting STAT6 may provide a novel therapeutic strategy for fibrotic kidney disease.

scholarly journals Serum and Ectopic Endometrium from Women with Endometriosis Modulate Macrophage M1/M2 Polarization via the Smad2/Smad3 Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Mei-Fang Nie ◽  
Qi Xie ◽  
Ya-Hong Wu ◽  
Hua He ◽  
Lu-Jie Zou ◽  
...  
Keyword(s):  
Conditioned Medium ◽  
Molecular Mechanisms ◽  
Macrophage Polarization ◽  
Leukemia Cell ◽  
M2 Macrophage ◽  
Monocytic Leukemia ◽  
Serum Samples ◽  
Endometrial Stromal Cells ◽  
M2 Polarization ◽  
M2 Macrophage Polarization

Objective. This study investigated the alterations in macrophage polarization in patients with endometriosis as well as the underlying molecular mechanisms. Methods. Peritoneal washings, serum samples, and endometrial tissues were collected from endometriosis patients and control subjects. Endometrial stromal cells (ESCs) were isolated from endometrial tissue, and conditioned medium was prepared by treating ESCs with or without various concentrations of interleukin- (IL-) 6, estrogen, or progestin. The frequencies of CD86+ and CD163+ cells and expression levels of these markers as well as the cytokines IL-12 and IL-10 were measured in THP-1- (human monocytic leukemia cell) derived macrophages. Results. There was a decrease in the percentage of CD86+ macrophages in the peritoneal wash solution of patients with endometriosis. Ectopic endometrial homogenates could promote M1 to M2 macrophage polarization in response to lipopolysaccharide (LPS), as evidenced by the increased percentage of CD163+ macrophages and increased IL-10 expression as well as a decreased percentage of CD86+ cells and lower IL-12 expression. In contrast, addition of serum from women with endometriosis to THP-1 cells resulted in the polarization of macrophages towards both M1 and M2 phenotypes. Upregulation of Smad2/Smad3 in macrophages upon exposure to eutopic and ectopic endometrial homogenates as well as serum of women with endometriosis was observed, and blockage of Smad2/Smad3 with their inhibitor SB431542 could reverse the macrophage polarization from M1 to M2. Conditioned medium induced by IL-6, but neither estrogen nor progestin, could facilitate M2 polarization. Neutralization of IL-6 diminished macrophage M2 polarization in endometriosis. Conclusion. This study provides detailed evidence supporting alterations in M1 to M2 macrophage polarization that may contribute to the initiation as well as progression of endometriosis.

Tenascin-C accelerates adverse ventricular remodelling after myocardial infarction by modulating macrophage polarization

2018 ◽  
Vol 115 (3) ◽  
pp. 614-624 ◽  
Author(s):  
Taizo Kimura ◽  
Kazuko Tajiri ◽  
Akira Sato ◽  
Satoshi Sakai ◽  
Zheng Wang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Matrix Protein ◽  
Molecular Mechanisms ◽  
Macrophage Polarization ◽  
Left Ventricular ◽  
Extracellular Matrix Protein ◽  
M2 Macrophage ◽  
Ventricular Remodelling ◽  
Tenascin C ◽  
M2 Macrophage Polarization

Abstract Aims Tenascin-C (TN-C) is an extracellular matrix protein undetected in the normal adult heart, but expressed in several heart diseases associated with inflammation. We previously reported that serum TN-C levels of myocardial infarction (MI) patients were elevated during the acute stage, and that patients with high peak TN-C levels were at high risk of left ventricular (LV) remodelling and poor outcome, suggesting that TN-C could play a significant role in the progression of ventricular remodelling. However, the detailed molecular mechanisms associated with this process remain unknown. We aimed to elucidate the role and underlying mechanisms associated with TN-C in adverse remodelling after MI. Methods and results MI was induced by permanent ligation of the coronary artery of TN-C knockout (TN-C-KO) and wild type (WT) mice. In WT mice, TN-C was expressed at the borders between intact and necrotic areas, with a peak at 3 days post-MI and observed in the immediate vicinity of infiltrating macrophages. TN-C-KO mice were protected from ventricular adverse remodelling as evidenced by a higher LV ejection fraction as compared with WT mice (19.0 ± 6.3% vs. 10.6 ± 4.4%; P < 0.001) at 3 months post-MI. During the acute phase, flow-cytometric analyses showed a decrease in F4/80+CD206lowCD45+ M1 macrophages and an increase in F4/80+CD206highCD45+ M2 macrophages in the TN-C-KO heart. To clarify the role of TN-C on macrophage polarization, we examined the direct effect of TN-C on bone marrow-derived macrophages in culture, observing that TN-C promoted macrophage shifting into an M1 phenotype via Toll-like receptor 4 (TLR4). Under M2-skewing conditions, TN-C suppressed the expression of interferon regulatory factor 4, a key transcription factor that controls M2-macrophage polarization, via TLR4, thereby inhibiting M2 polarization. Conclusion These results suggested that TN-C accelerates LV remodelling after MI, at least in part, by modulating M1/M2-macrophage polarization.

Matrix metalloproteinase-8 (MMP8) modulates M2 macrophage polarization and molecular mechanisms involved

2014 ◽  
Vol 237 (2) ◽  
pp. e15 ◽  
Author(s):  
Guanmei Wen ◽  
Qishan Chen ◽  
Le Anh Luong ◽  
Arif Mustafa ◽  
Ye Shu ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Molecular Mechanisms ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
M2 Macrophage Polarization

Abstract 410: Interleukin-21 Promotes Pulmonary Arterial Hypertension Through M2 Macrophage Polarization

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Yoshikazu Nakaoka ◽  
Takahiro Hashimoto-Kataoka ◽  
Mikiyasu Shirai ◽  
Yasushi Sakata
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Macrophage Polarization ◽  
Animal Experiments ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Pulmonary Arterial ◽  
M2 Macrophage Polarization

Interleukin-6 (IL-6) is a multifunctional proinflammatory cytokine that is elevated in the serum of pulmonary arterial hypertension (PAH) patients and can predict the survival of idiopathic (I)PAH patients. Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a novel downstream target of IL-6-signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Furthermore, the hypoxia-induced upregulation of IL-17 and IL-21, which are primarily produced by Th17 cells, was also ameliorated by IL-6 blockade in mice. Whereas IL-17 blockade with an anti-IL-17 neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. Consistently, IL-21 indeed promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Moreover, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH through M2 macrophage polarization, downstream of IL-6-signaling. IL-6/Th17/IL-21-signaling axis may be a novel potential target for treating PAH.

scholarly journals Complement C3 exacerbates renal interstitial fibrosis by facilitating the M1 macrophage phenotype in a mouse model of unilateral ureteral obstruction

2019 ◽  
Vol 317 (5) ◽  
pp. F1171-F1182 ◽  
Author(s):  
Jiong Cui ◽  
Xiaoting Wu ◽  
Yankun Song ◽  
Yi Chen ◽  
Jianxin Wan
Keyword(s):  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Macrophage Polarization ◽  
Unilateral Ureteral Obstruction ◽  
Complement C3 ◽  
M2 Macrophage ◽  
Inflammatory Factor ◽  
Renal Interstitial Fibrosis ◽  
M1 Polarization

The impact of the renal microenvironment on macrophage phenotype determination can contribute to the progression or resolution of renal fibrosis. Although the complement proteins affect macrophage polarization, whether complement component 3 (C3) can induce macrophage polarization and regulate renal interstitial fibrosis remains undetermined. In the present study, we investigated the contribution of C3 on macrophage polarization and renal fibrosis in C3-deficient mice with unilateral ureteral obstruction and bone marrow-derived macrophages. C3-deficient mice exhibited attenuated renal fibrosis and ameliorated peritubular capillary rarefaction. Lack of C3 contributed to M2 macrophage polarization, increased IL-10 and VEGF164, and decreased TNF-α and soluble VEGF receptor 1 expression in the obstructed kidneys at the early stages of unilateral ureteral obstruction. C3a facilitated LPS-induced M1 polarization and inflammatory factor production in bone marrow-derived macrophages in vitro, accompanied by increased ERK, NF-κB, and STAT1 phosphorylation. The ERK-specific inhibitor PD98059 inhibited the phosphorylation of ERK, NF-κB, and STAT1 and attenuated M1 polarization-related inflammatory factor production. Furthermore, the culture supernatant from M1 macrophages and C3a-treated M2 macrophages were more detrimental to angiogenesis compared with M2 macrophage supernatants. Thus, complement C3 exacerbates renal interstitial fibrosis by facilitating macrophage M1 polarization, promoting proinflammatory cytokine expression, and deteriorating peritubular capillary rarefaction in the kidney.

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