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Qishen Granule Improved Cardiac Remodeling via Balancing M1 and M2 Macrophages.

ABSTRACT: Macrophages play a pivotal role in myocardial remodeling (MR) process which could eventually lead to heart failure. Splenic monocytes could be mobilized and recruited under inflammatory conditions and differentiated into different types of macrophages in heart tissues. Inflammatory M1 macrophages could aggravate tissue damage whereas M2 macrophages could promote angiogenesis and tissue repair process. Unbalanced ratio of M1/M2 macrophages may eventually lead to adverse remodeling. Therefore, regulating differentiation and activities of macrophages are potential strategies for the management of myocardial remodeling. Qishen Granule (QSG) is an effective Chinese medicine for treating heart failure. Our previous studies demonstrated that QSG could inhibit myocardial fibrosis through regulating secretion of cytokines and activation of macrophages. However, the detailed effects of QSG on had not been elucidated yet. In this study, we aimed to explore the effect of QSG on the release of splenic monocytes, the recruitment of monocytes into heart tissues and the differentiation of macrophages under ischemic conditions. Our results showed that QSG could suppress the release of monocytes from the spleen and recruitment of monocytes to heart tissues via inhibiting splenic angiotensin (Ang) II/AT1-cardiac monocyte chemotactic protein (MCP)-1/CC chemokine receptor 2 (CCR2) pathway. The anti-fibrotic effect of QSG was exerted by inhibiting M1 macrophage-activated transforming growth factor (TGF)-?1/Smad3 pathway. Meanwhile, QSG could promote angiogenesis by promoting differentiation of M1 macrophages into M2 macrophages. Our results suggest that compounds of Chinese medicine have synergistic effects on cardiac and splenic organs through regulating differentiation of monocytes/macrophages in inhibiting myocardial remodeling.

SUBMITTER: Lu W

PROVIDER: S-EPMC6886583 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Project description:Macrophage polarization is increasingly recognised as an important pathogenetic factor in inflammatory and neoplastic diseases. Proinflammatory M1 macrophages promote T helper (Th) 1 responses and show tumoricidal activity. M2 macrophages contribute to tissue repair and promote Th2 responses. CD68 and CD163 are used to identify macrophages in tissue sections. However, characterisation of polarised macrophages in situ has remained difficult. Macrophage polarisation is regulated by transcription factors, pSTAT1 and RBP-J for M1, and CMAF for M2. We reasoned that double-labelling immunohistochemistry for the detection of macrophage markers together with transcription factors may be suitable to characterise macrophage polarisation in situ. To test this hypothesis, we have studied conditions associated with Th1- and Th2-predominant immune responses: infectious mononucleosis and Crohn's disease for Th1 and allergic nasal polyps, oxyuriasis, wound healing and foreign body granulomas for predominant Th2 response. In all situations, CD163+ cells usually outnumbered CD68+ cells. Moreover, CD163+ cells, usually considered as M2 macrophages, co-expressing pSTAT1 and RBP-J were found in all conditions examined. The numbers of putative M1 macrophages were higher in Th1- than in Th2-associated diseases, while more M2 macrophages were seen in Th2- than in Th1 related disorders. In most Th1-related diseases, the balance of M1 over M2 cells was shifted towards M1 cells, while the reverse was observed for Th2-related conditions. Hierarchical cluster analysis revealed two distinct clusters: cluster I included Th1 diseases together with cases with high numbers of CD163+pSTAT1+, CD68+pSTAT1+, CD163+RBP-J+ and CD68+RBP-J+ macrophages; cluster II comprised Th2 conditions together with cases displaying high numbers of CD163+CMAF+ and CD68+CMAF+ macrophages. These results suggest that the detection of pSTAT1, RBP-J, and CMAF in the context of CD68 or CD163 expression is a suitable tool for the characterisation of macrophage polarisation in situ. Furthermore, CD163 cannot be considered a reliable M2 marker when used on its own.

Project description:BackgroundToll-like receptors (TLRs) and macrophages play an important role in rheumatoid arthritis (RA). Currently, it is not clear whether inflammatory M1 or anti-inflammatory M2 predominate among the resident macrophages in the synovium. In the present study, we set out to investigate the impact of TLR stimulation on monocyte-derived M1 and M2 macrophage function and phenotype by mimicking the exposure to abundant TLR agonists as occurs in the context of RA. The response of macrophage subsets to TLR2 and TLR4 activation was evaluated on cluster of differentiation (CD) marker profile; cytokine secretion; gene expression; and NF-?B, interferon regulatory factors 3 and 7 (IRF3/7), and mitogen-activated protein kinase (MAPK) activation.MethodsHuman monocytes were isolated from peripheral blood of healthy individuals and patients with RA and differentiated into M1-like and M2-like macrophages by granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF), respectively. Cells were either (1) stimulated with TLR ligands Pam3 or lipopolysaccharide (LPS) or (2) classically activated via interferon (IFN)-?/LPS. Cytokine production was measured by enzyme-linked immunosorbent assay, and gene expression was measured by qPCR. Cells were stained for CD markers and analyzed by fluorescence-activated cell sorting. NF-?B, IRF3/7, and MAPKs were detected by Western blotting.ResultsMonocyte-derived macrophages of healthy donors (HD) or patients with RA displayed comparable subset-specific phenotypes upon exposure to TLR agonists. CD14 and CD163 marker expression on M2 macrophages did not change upon TLR2 and TLR4 engagement. By contrast, M2 gene markers HMOX1, FOLR2, and SLC40A1 were decreased. Importantly, M2 macrophages derived from HD or patients with RA showed both a decreased ratio of interleukin (IL)-10/IL-6 and IL-10/IL-8 upon stimulation with TLR2 ligand Pam3 compared with TLR4 ligand LPS. Gene expression of TLR2 was increased, whereas TLR4 expression was decreased, by TLR ligand stimulation. MAPKs p38, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase were activated more strongly in M2 than in M1 macrophages by Pam3 or LPS.ConclusionsWe show that the anti-inflammatory activity of M2 macrophages is reduced in the presence of abundant TLR2 ligands without significant changes in cell surface markers. Thus, the classical M1/M2 paradigm based on cellular markers does not apply to macrophage functions in inflammatory conditions such as RA.

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Qishen Granule Improved Cardiac Remodeling via Balancing M1 and M2 Macrophages.

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