(+)-Borneol improves the efficacy of edaravone against DSS-induced colitis by promoting M2 macrophages polarization via JAK2-STAT3 signaling pathway

doi:10.1016/j.intimp.2017.10.002

International Immunopharmacology

Volume 53, December 2017, Pages 1-10

https://doi.org/10.1016/j.intimp.2017.10.002 Get rights and content

Highlights

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(+)-Borneol improved the efficacy of EDA against DSS-induced colitis.
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C.EDA inhibited the infiltration of M1 macrophages, promoted the polarization of M2 macrophages and protected the integrity of colon tissue.
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C.EDA greatly promoted M2 macrophages polarization in Raw264.7 cells
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C.EDA strengthened the activation of JAK2-STAT3 signaling pathway and promoted STAT3 nuclear translocation
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STAT3-specific RNA interference successfully abolished the effects of C.EDA on inducing M2 macrophages polarization

Abstract

Compound edaravone injection (C.EDA), a compound preparation composed of edaravone (EDA) and (+)-Borneol with the mass ratio of 4: 1, displays a better anti-inflammatory activity than EDA. However, its precise mechanism remains to be further studied. In this work, we investigated whether (+)-Borneol could improve the efficacy of EDA against DSS-induced colitis. We found that C.EDA at 7.5 and 15 mg/kg could significantly relieve the disease activity index (DAI) and reduce the loss of body weight and colon length in a dose-dependent manner, while EDA or (+)-Borneol alone only had moderate effects even at the highest dose. Additionally, ELISA revealed that C.EDA could more dramatically decrease the protein levels of inflammatory cytokines and increase the levels of anti-inflammatory cytokine than EDA or (+)-Borneol alone both in colon tissues and serum. H&E staining and IHC assay also indicated that C.EDA exhibited more prominent effects on increasing the population of M2 macrophages, decreasing M1 macrophages infiltration and protecting intestinal barrier integrity. Furthermore, in vitro studied demonstrated that C.EDA, EDA or (+)-Borneol failed in inhibiting M1 macrophages activation but could specifically induce the activation of M2 macrophages in a STAT3-dependent manner. Knockdown the expression of STAT3 successfully abolished the effect of C.EDA and EDA on promoting M2 macrophages activation. Consistent with in vivo study, C.EDA exhibited a more efficient ability of inducing M2 macrophages polarization and STAT3 activation than EDA or (+)-Borneol alone in vitro. In conclusion, we confirmed that (+)-Borneol improved the efficacy of EDA against DSS-induced colitis by promoting M2 macrophages polarization via JAK2-STAT3 signaling pathway.

Graphical abstract

Introduction

Crohn's disease and ulcerative colitis, also named inflammatory bowel diseases (IBDs) with poor response to clinical treatment, are linked with high mortality and have a great influence on the quality of individual's life due to pain, vomiting, diarrhea, and other socially undesired symptoms. The worldwide incidence of IBDs keeps increasing with a highest prevalence in Europe and Canada [1]. IBDs are structure diseases with underlying physical damages in the gut, often in the end of small intestine or colon, as detected by X-ray, endoscopy, surgery, or biopsy [2]. Although the exact etiology of IBDs remains unknown, it is widely accepted that IBDs are developed in genetically susceptible individuals with abnormal immune responses against the microorganisms in the intestinal flora [3]. Thus, IBDs are a class of autoimmune diseases resulting from the healthy elements of body's digestive system attacked by the excessive activation of their own immune systems [4].

Macrophages are key mediators of immune system and play central roles in maintaining a steady state of intestinal homoeostasis by removing apoptotic cells debris and fighting against pathogens [5], [6]. Depending on the environmental signals, macrophages are generally polarized into two functionally opposite forms: classically activated (M1) macrophages and alternatively activated (M2) macrophages [7]. M1 macrophages induced by IFN-γ, lipopolysaccharide (LPS), TNF-a, and granulocyte-macrophage colony-stimulating factor (GM-CSF) could triger Th1 and Th17 responses via producing high levels of inflammatory cytokines including TNF-a, IL-6, IL-1β, IL-12 and IL-23 [8]. While M2 macrophages polarized by IL-4, IL-13 and macrophage colony-stimulating factor (M-CSF) participate in Th2 response, exhibiting anti-inflammation profile through upregulating the expression of IL-10, arginase 1 (Arg-1) and CD206 antigen [9]. Interestingly enough, studies has proved that M1 macrophages and M2 macrophages are interchangeably. This switch makes macrophages play a dual role in orchestrating the lasting inflammation and onset of healing and repairing [10]. Although the functions of M1 and M2 macrophages during the initiation and development IBDs have not yet been well identified, scientists found that experimental IBDs could be greatly ameliorated by the induction of intestinal macrophages polarized to M2 macrophages via small molecules or specific antibodies [11].

JAK2-STAT3 signaling pathway in macrophages involves in immunosuppression [12]. Actually, signal transducer and activator of transcription 3 (STAT3) is regarded as a key signaling molecule for macrophage polarization to M2 macrophages [13]. STAT3 signaling pathway is much more highly activated in M2 macrophages than in M1 macrophages [14]. Researches also displayed that STAT3 knockout macrophages stayed on a higher pro-inflammation state via releasing a large amount of pro-inflammatory cytokines, such as TNF-a, IL-6, IL-1β [15]. STAT3 activation promotes production of various anti-inflammatory cytokines including IL-10, which inhibits functional dendritic cells (DC) maturation and increases population of T regulatory cells (Treg) [16].

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, EDA) is a free radical scavenger which exhibits promising activities in preventing neuro-inflammation, liver injury and antioxidant, reported by a variety of studies [17]. Compound edaravone injection (C.EDA) is a compound preparation composed of edaravone and borneol with the mass ratio of 4: 1 [18]. C.EDA has been finished Phase III clinical trial for Acute Ischemic Stroke approved by CFDA in 2016 [19]. C.EDA has been reported to display a better activity than EDA alone in fighting against inflammation in multiple mouse models [20]. However, the activity of C.EDA in fighting against colitis has not yet been tested. In this study, we assessed the effects of C.EDA, EDA and (+)-Borneol on a mouse model of experimental colitis induced by dextran sulfate sodium (DSS) administration and the polarization of mouse macrophage RAW264.7 cells. These results revealed that (+)-Borneol could improve the efficacy of EDA against DSS-induced colitis by promoting M2 macrophages polarization in a STAT3-depedent manner. Our study provided a basis for the clinical use of C.EDA in treating IBDs.

Section snippets

Reagents

C.EDA (10 mg/5 mL), EDA (10 mg/5 mL) and (+)-Borneol were provided by Jiangsu Simcere Pharmaceutical Co., Ltd.. For cell treatment, C.EDA and EDA were diluted to 10 mM with PBS. (+)-Borneol were dissolved in PBS (0.5 mg/mL, 32 mM) and used as 100 ×. CCK-8 and LPS were obtained from Sigma-Aldrich (St Louis, USA). Recombinant murine IFN-γ, IL-4 and IL-13 was purchased from PeproTech (Rocky Hill, USA). Lipofectamine® RNAiMAX was obtained from Invitrogen (Burlington, ON). Antibodies used for Western

(+)-Borneol improved the efficacy of EDA against DSS-induced colitis

In order to study whether (+)-Borneol could improves the efficacy of EDA on taming colon inflammation, we used a mouse model of DSS-induced experimental colitis to evaluate the therapeutic effects. Mice were challenged with 2.5% DSS in drinking water for 7 days and then treated with indicated does of C.EDA, EDA or (+)-Borneol for another 10 days. The chemical structure of EDA and (+)-Borneol were shown in Fig. 1A. Compared with DSS-treated group, C.EDA at 7.5 and 15 mg/kg could significantly block

Discussion

Nature Borneol, only contains (+)-Borneol, is a traditional Chinese medicine often used to increase the therapeutic effect of various drugs by improving their permeability and increasing drug concentrations in the brain [23], [24]. C.EDA is a compound preparation composed of edaravone and borneol with the mass ratio of 4: 1 and has been finished Phase III clinical trial for Acute Ischemic Stroke approved by CFDA in 2016, having a better activity than EDA alone in fighting against sepsis.

Conflict

The authors declare that they have no conflicts of interest concerning this article.

Acknowledgements

This work was supported by National Natural Science Foundation of China (Nos. 81673487, 81473221), Natural Science Foundation of Jiangsu Province (BK20161399) and the Fundamental Research Funds for the Central Universities (020814380076).

Author contribution

Xiong Zhang and Fang Xu contributed equally. Study conception and design: X. Wu and Q. Xu; acquisition, analysis and/or interpretation of data: X. Zhang and F. Xu; drafting/revision of the work for intellectual content and context: X. Wu; final approval and overall responsibility for the published work: X. Wu and Q. Xu.

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A single intra-arterial administration of edaravone dexborneol can improve neurobehavioral function and alleviate cerebral injury in acute ischemic stroke rats through anti-inflammatory and free radical scavenging effects.
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Citation Excerpt :
Chuanxiong Rhizoma, Styrax and Musk have been proved to have the role of anti-myocardial ischemia (Liu et al., 2016; Wang et al., 2019; Wu et al., 2011). Besides, Borneolum Syntheticum as an adjuvant has been reported to provide new possibilities for the treatment of atherosclerosis (Zhang et al., 2017). Muscone, tetrahydropalmatine, ginsenoside, tetramethylpyrazine, cinnamic acid and borneol have been reported as important bioactive components relevant to treatment of CHD.
Shexiang Xintongning tablet (SXXTN) is a traditional Chinese medicine (TCM) preparation for the treatment of coronary heart disease (CHD) angina pectoris. However, due to the complexity of the compounds in SXXTN, the active chemical components responsible for the therapeutic effect are still ambiguous. The purpose of our study was to characterize the chemical profile of SXXTN and quantify the representative chemicals. The high-performance liquid chromatography coupled with time-of-flight mass spectrometry (HPLC-QTOF MS) method and gas chromatograph coupled with mass spectrometry (GC–MS) method were utilized to identify the chemical constituents of SXXTN. A total of 140 compounds including alkaloids, ginsenosides, organic acids, esters, triterpenes, phthalides and amino acid were identified in accordance with their retention times, accurate masses and characteristic MS/MS fragment patterns. Forty-four volatile components were characterized by GC–MS through NIST database matching. In the further research of quantitative analysis, 40 non-volatile compounds and 17 volatile compounds were determined and successfully applied for detecting in 7 batches of SXXTN samples by high performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry (HPLC-QQQ MS) and gas chromatograph coupled with triple-quadrupole tandem mass spectrometry (GC-QQQ MS) in multiple reaction monitoring (MRM) mode, respectively. The quantitative methods were verified in linearity, precision, repeatability stability and recovery. The above results indicated that the established method was practical and reliable for synthetical quality evaluation of SXXTN. In addition, our study might supplement the chemical evidence for disclosing the material basis of its therapeutic effects.
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followed by secondary antibody at room temperature. Cells immunofluorescence analysis was performed as previous way (Zhang et al., 2017). Briefly, RAW264.7 cells were fixed after treatment, then used 0.2% triton X-100 for permeabilized, further, blocked with 5%BSA.
Atopic dermatitis (AD), a common inflammatory skin disorder, severely affects the life quality of patients and renders heavy financial burden on patient's family. The Chinese medicine Viola yedoensis Makino formula (VYAC) has been widely used for treating various skin disorders. Previous studies have reported that VYAC is effective in relieving DNCB-induced AD and inflammation. However, the anti-inflammatory mechanism of VYAC is still ill-defined and poorly understood. This study aims to investigate the therapeutic effects of VYAC on DNCB-induced AD and to elucidate the underlying anti-inflammatory mechanisms.
VYAC were extracted with 70% ethanol and lyophilized for use. AD mice were established by DNCB. The therapeutic effects of VYAC were evaluated by oral administration VYAC (150, 300 and 600 mg/kg) daily in vivo. The histopathological and immunohistochemistry were used to analyze skin lesion and macrophages infiltration, RT-qPCR and Elisa were used to analyze the inflammatory factors in skin tissues and serum. To explore the underlying mechanism of VYAC against AD in vitro. RAW264.7 cells and bone-marrow-derived macrophages (BMDMs) were employed for macrophage polarization analysis. Flow cytometer, immunofluorescence and western blot were used to analyze M2 macrophages markers. STAT3 siRNA were transfected into both cells to validate the effects of VYAC-induced macrophages M2 polarization via JAK2/STAT3 signaling pathway.
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¹: The authors contributed equally to this work.

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(+)-Borneol improves the efficacy of edaravone against DSS-induced colitis by promoting M2 macrophages polarization via JAK2-STAT3 signaling pathway

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Reagents

(+)-Borneol improved the efficacy of EDA against DSS-induced colitis

Discussion

Conflict

Acknowledgements

Author contribution

Mol. Cell

Cell Rep.

Eur. J. Pharmacol.

Biochem. Pharmacol.

Eur. J. Pharm. Sci.

Cell Rep.

Mol. Immunol.

Cell Rep.

Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review

Gastroenterology

Musculoskeletal manifestations in inflammatory bowel disease: a revisit in search of immunopathophysiological mechanisms

J. Clin. Gastroenterol.

Overview of cytokines and nitric oxide involvement in immuno-pathogenesis of inflammatory bowel diseases

World J. Gastrointest. Pharmacol. Ther.

Inflammatory bowel disease: clinical aspects and treatments

J. Inflamm. Res.

Downregulated expression of microRNA-124 in pediatric intestinal failure patients modulates macrophages activation by inhibiting STAT3 and AChE

Cell Death Dis.

Diet-dependent, microbiota-independent regulation of IL-10-producing lamina propria macrophages in the small intestine

Sci Rep

Macrophage plasticity and polarization: in vivo veritas

J. Clin. Invest.

Altered macrophage differentiation and immune dysfunction in tumor development

J. Clin. Invest.

Tissue damage drives co-localization of NF-kappaB, Smad3, and Nrf2 to direct Rev-erb sensitive wound repair in mouse macrophages

elife

FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling

Cancer Res.