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.

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.

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.

scholarly journals IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation

2017 ◽  
Vol 112 (3) ◽  
Author(s):  
Mira Jung ◽  
Yonggang Ma ◽  
Rugmani Padmanabhan Iyer ◽  
Kristine Y. DeLeon-Pennell ◽  
Andriy Yabluchanskiy ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Fibroblast Activation ◽  
M2 Macrophage Polarization

scholarly journals Enhanced M1 and Impaired M2 Macrophage Polarization and Reduced Mitochondrial Biogenesis via Inhibition of AMP Kinase in Chronic Kidney Disease

2015 ◽  
Vol 36 (1) ◽  
pp. 358-372 ◽  
Author(s):  
Cong Li ◽  
Xiao Yan Ding ◽  
Dong Mei Xiang ◽  
Jie Xu ◽  
Xiang Lan Huang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Mitochondrial Biogenesis ◽  
Ex Vivo ◽  
Macrophage Polarization ◽  
Adenosine Monophosphate ◽  
M2 Macrophage ◽  
Macrophages Polarization ◽  
M2 Macrophage Polarization ◽  
Factor Α

Background: Macrophage polarization plays a pivotal role in the process of inflammation which is common in chronic kidney disease (CKD). Macrophages polarization under the condition of CKD remains poorly understood. Here we tested the hypothesis that CKD promotes macrophage M1 polarization. Methods: A rat model of CKD was established by reduced renal mass (RRM). Polarization of macrophages was induced in ex vivo macrophages from RRM rats and cultured ones under the condition of uremic serum. The markers were evaluated by RT-PCR, western blot, and flow cytometer. Results: Our data showed that macrophages from RRM rats displayed enhanced M1 and impaired M2 polarization as revealed by increased M1 markers (tumor necrosis factor α, IL-6, IL-12p40, nitric oxide) and decreased M2 markers (IL-10, CD206, arginase activity) in response to LPS and IL-4 induction, respectively. Treatment with uremic sera in peritoneal and bone marrow derived macrophages from normal rats led to similar results. Moreover, macrophages from RRM rats and cultured under the condition of uremic sera had reduced mitochondrial biogenesis. The disturbed macrophage polarization and mitochondrial biogenesis were accompanied by reduced activity of adenosine monophosphate-activated protein (AMP)-activated kinase (AMPK). Enhancing activation of AMPK restored mitochondrial biogenesis and M2 macrophage polarization. Conclusion: These observations suggest that CKD disturbs macrophage polarization and mitochondrial biogenesis through inhibition of AMPK. This might provide a novel therapeutic strategy for intervention of chronic inflammation in CKD.

scholarly journals M2 macrophage polarization in chronic spontaneous urticaria refractory to antihistamine treatment

2021 ◽  
Author(s):  
Roberta F.J. Criado ◽  
Paulo Ricardo Criado ◽  
Carla Pagliari ◽  
Mirian N. Sotto ◽  
Carlos D'Apparecida Machado Filho ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Chronic Spontaneous Urticaria ◽  
M2 Macrophage ◽  
M2 Macrophage Polarization

Nucleolin Improves Heart Function During Recovery From Myocardial Infarction by Modulating Macrophage Polarization

2021 ◽  
pp. 107424842198957
Author(s):  
Yuting Tang ◽  
Xiaofang Lin ◽  
Cheng Chen ◽  
Zhongyi Tong ◽  
Hui Sun ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Early Phase ◽  
Heart Function ◽  
Macrophage Polarization ◽  
Late Phase ◽  
Macrophage Infiltration ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Macrophage ◽  
M2 Macrophage Polarization ◽  
Nucleolin Expression

Background: Nucleolin has multiple functions within cell survival and proliferation pathways. Our previous studies have revealed that nucleolin can significantly reduce myocardial ischemia-reperfusion injury by promoting myocardial angiogenesis and reducing myocardial apoptosis. In this study, we attempted to determine the role of nucleolin in myocardial infarction (MI) injury recovery and the underlying mechanism. Methods: Male BALB/c mice aged 6–8 weeks were used to set up MI models by ligating the left anterior descending coronary artery. Nucleolin expression in the heart was downregulated by intramyocardial injection of a lentiviral vector expressing nucleolin-specific small interfering RNA. Macrophage infiltration and polarization were measured by real-time polymerase chain reaction, flow cytometry, and immunofluorescence. Cytokines were detected by enzyme-linked immunosorbent assay. Results: Nucleolin expression in myocardium after MI induction decreased a lot at early phase and elevated at late phase. Nucleolin knockdown impaired heart systolic and diastolic functions and decreased the survival rate after MI. Macrophage infiltration increased in the myocardium after MI. Most macrophages belonged to the M1 phenotype at early phase (2 days) and the M2 phenotype increased greatly at late phase after MI. Nucleolin knockdown in the myocardium led to a decrease in M2 macrophage polarization with no effect on macrophage infiltration after MI. Furthermore, Notch3 and STAT6, key regulators of M2 macrophage polarization, were upregulated by nucleolin in RAW 264.7 macrophages. Conclusions: Lack of nucleolin impaired heart function during recovery after MI by reducing M2 macrophage polarization. This finding probably points to a new therapeutic option for ischemic heart disease.

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