Harmine Alleviated Sepsis-Induced Cardiac Dysfunction by Modulating Macrophage Polarization via the STAT/MAPK/NF-κB Pathway

Ruan, Weibin; Ji, Xinyun; Qin, Yating; Zhang, Xinxin; Wan, Xiaoning; Zhu, Chi; Lv, Chao; Chen, Hu; Lü, Li; Guo, Xiaomei

doi:10.3389/fcell.2021.792257

Cited by 20 publications

(13 citation statements)

References 46 publications

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“…The MAPK/NF-κB/STAT pathway plays a crucial role in macrophages, which can be affected by a variety of factors to change their phenotype and, thus, affect their function [ 15 , 16 , 19 , 33 ]. In line with previous reports [ 34 , 35 , 36 ], LPS + IFN-γ treatment significantly resulted in phosphorylation of ERK, p38, JNK, p50 and p65 ( Figure 6 A,C), and IL-4 treatment led to phosphorylation of Akt, STAT3 and STAT6 in THP-1 ( Figure 7 A), demonstrating the activation of the MAPK-NF-κB pathway or the Akt/STAT pathway in M1 or M2 macrophage polarization, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…It was reported that complete polarization of macrophages to the M1 type requires activation of the MAPK and NF-κB signaling pathways [ 19 , 27 , 31 , 61 ], and M2 macrophage polarization requires activation of the STAT signaling pathway [ 62 , 63 ]. To explore the signal transduction pathways underlying the regulatory effects of TcpC on M1/M2 polarization, the influence of TcpC on MAPK/NF-κB and Akt/STAT pathways was examined.…”

Section: Discussionmentioning

confidence: 99%

“…A number of transcriptional regulators participate in the differential activation of macrophages [ 12 , 13 , 14 ]. Macrophages are activated in response to infection, which is induced through NF-κB, mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) signaling pathways [ 15 , 16 , 17 , 18 , 19 ]. Activated macrophages can be polarized to a proinflammatory M1 phenotype or an anti-inflammatory M2 phenotype.…”

Section: Introductionmentioning

confidence: 99%

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TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection

Fang

et al. 2022

Cells

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TcpC is a multifunctional virulence factor of Uropathogenic Escherichia coli (UPEC). Macrophages can differentiate into two different subsets M1 and M2 that play distinct roles in anti-infection immunity. Here, we investigate the influence of TcpC on M1/M2 polarization and the potential mechanisms. Our data showed that M1 markers CD86 and iNOS were significantly inhibited, while the M2 markers CD163, CD206 and Arg-1 were enhanced in macrophages in kidneys from the TcpC-secreting wild-type CFT073 (CFT073wt)-infected pyelonephritis mouse model, compared with those in macrophages in kidneys from TcpC knockout CFT073 mutant (CFT073Δtcpc)-infected mice. CFT073wt or recombinant TcpC (rTcpC) treatment inhibits LPS + IFN-γ-induced CD80, CD86, TNF-α and iNOS expression, but promotes IL-4-induced CD163, CD206, Arg-1 and IL-10 expression in both human and mouse macrophage cell lines THP-1 and J774A.1. Moreover, rTcpC significantly attenuated LPS + IFN-γ-induced phosphorylation of p38, ERK, p50 and p65 but enhanced IL-4-induced phosphorylation of Akt and STAT6. These data suggest that TcpC inhibits M1 but promotes M2 macrophage polarization by down-regulation of p38, ERK/NF-κB and up-regulation of the Akt/STAT6 signaling pathway, respectively. Our findings not only illuminate the regulatory effects of TcpC on macrophage M1/M2 polarization and its related signaling pathways, but also provide a novel mechanism underlying TcpC-mediated immune evasion of macrophage-mediated innate immunity.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection

Fang

et al. 2022

Cells

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“…Western blot analysis was performed as previously described [ 15 ].Total protein was extracted from myocardial tissues using lysis buffer (Sigma-Aldrich, MD, USA). Proteins were separated on 10% SDS-PAGE and then transferred onto polyvinylidene fluoride (PVDF) membranes.…”

Section: Methodsmentioning

confidence: 99%

Transplantation of umbilical cord blood-derived mesenchymal stem cells as therapy for adriamycin induced-cardiomyopathy

Zhang¹,

Zhang²,

Yang³

et al. 2022

Bioengineered

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Umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) have been reported to possess cardioprotective effects in diseases. However, its effects on cardiomyopathy remain unclear. This study aimed to the therapeutic effects of UCBMSC transplantation on adriamycin (ADR)-induced cardiomyopathy. UCBMSCs isolated from human UCB were identified by detecting surface markers (CD29, CD90, CD34, and CD45) using flow cytometry. The effect of UCBMSCs on left ventricular end-diastolic dimension (LVEDD), left ventricular systolic end-diastolic diameter (LVESD), left ventricular ejection fraction (LVEF), and left ventricular fraction shortening (LVFS) were determined by echocardiography. Histological changes were observed by HE and Masson staining. The serum levels of collagen-I (Col-I), brain natriuretic peptide (BNP), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), CK-MB, interleukin (IL)-6, IL-10, and tumor necrosis factor alpha (TNF-α) were measured by corresponding kits. The protein levels of IL-6, IL-10, and TNF-α were measured by Western blotting. The isolated UCBMSCs manifested the positive expression of CD29 and CD90, and the negative expression of CD34 and CD45. UCBMSC transplantation significantly reduced LVEDD and LVESD, and increased LVEF and LVFS in ADR-induced cardiomyopathy model rats. Cardiac injury and high collagen deposition in model rats were alleviated by UCBMSC treatment. Moreover, UCBMSCs decreased the serum levels of Col-I, BNP, AST, LDH, CK, CK-MB, IL-6, IL-10, and TNF-α in model rats. Overall, UCBMSCs exert the therapeutic effects on ADR-induced cardiomyopathy through recovering the myocadiac function and alleviating the inflammatory response.

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“…To mimic the crosstalk between macrophages and cardiomyocytes, different co-culture models are commonly utilized [ 24 , 25 , 26 ]. However, due to the fact that cardiomyocytes are directly or indirectly exposed to conditioned medium of proinflammatory macrophages containing cytokines, growth factors, hormones, eRNA, and EVs, the underlying pathomechanisms are highly complex and require further studies [ 17 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

DAMPs Released from Proinflammatory Macrophages Induce Inflammation in Cardiomyocytes via Activation of TLR4 and TNFR

Neu

Thiele

Horr

et al. 2022

IJMS

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Cardiac dysfunction is a life-threatening complication in sepsis. Upon infection and cardiac stress, the cardiac macrophage population expands. Recruited macrophages exhibit a predominantly proinflammatory phenotype and release danger-associated molecular patterns (DAMPs) that contribute to cardiac dysfunction. However, the underlying pathomechanisms are highly complex and not fully understood. Here, we utilized an indirect macrophage–cardiomyocyte co-culture model to study the effects of proinflammatory macrophages on the activation of different cardiac receptors (TLR3, TLR4, and TNFR) and their role in cardiac inflammation and caspase-3/7 activation. The stimulation of cardiomyocytes with conditioned medium of LPS-stimulated macrophages resulted in elevated IL-6 protein concentrations and relative IL-6 and TNFα mRNA levels. Conditioned medium from LPS-stimulated macrophages also induced NFκB translocation and increased caspase-3/7 activation in cardiomyocytes. Analyzing the role of different cardiac receptors, we found that TLR4 and TNFR inhibition reduces cardiac inflammation and that the inhibition of TNFR prevents NFκB translocation into the nuclei of cardiomyocytes, induced by exposure to conditioned medium of proinflammatory macrophages. Moreover, we demonstrated that TLR3 inhibition reduces macrophage-mediated caspase-3/7 activation. Our results suggest that the immune response of macrophages under inflammatory conditions leads to the release of DAMPs, such as eRNA and cytokines, which in turn induce cardiomyocyte dysfunction. Thus, the data obtained in this study contribute to a better understanding of the pathophysiological mechanisms of cardiac dysfunction.

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Harmine Alleviated Sepsis-Induced Cardiac Dysfunction by Modulating Macrophage Polarization via the STAT/MAPK/NF-κB Pathway

Cited by 20 publications

References 46 publications

TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection

TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection

Transplantation of umbilical cord blood-derived mesenchymal stem cells as therapy for adriamycin induced-cardiomyopathy

DAMPs Released from Proinflammatory Macrophages Induce Inflammation in Cardiomyocytes via Activation of TLR4 and TNFR

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