The effect of macrophage polarization on the expression of the oxytocin signalling system in enteric neurons

Abstract Background The aim of the current study was to investigate the effect of macrophage polarization on the expression of oxytocin (OT) and the oxytocin receptor (OTR) in enteric neurons. Methods In this study, we used a classic colitis model and D-mannose model to observe the correlation between macrophage polarization and OT signalling system. In order to further demonstrate the effect of macrophages, we examined the expression of OT signalling system after depletion of macrophages. Results The data showed that, in vitro, following polarization of macrophages to the M1 type by LPS, the macrophage supernatant contained proinflammatory cytokines (IL-1β, IL-6 and TNF-α) that inhibited the expression of OT and OTR in cultured enteric neurons; following macrophage polarization to the M2 type by IL4, the macrophage supernatant contained anti-inflammatory cytokines (TGF-β) that promoted the expression of OT and OTR in cultured enteric neurons. Furthermore, M1 macrophages decreased the expression of the OT signalling system mainly through STAT3/NF-κB pathways in cultured enteric neurons; M2 macrophages increased the expression of the OT signalling system mainly through activation of Smad2/3 and inhibition of the expression of Peg3 in cultured enteric neurons. In a colitis model, we demonstrated that macrophages were polarized to the M1 type during the inflammatory phase, with significant decreased in the expression of OT and OTR. When macrophages were polarized to the M2 type during the recovery phase, OT and OTR expression increased significantly. In addition, we found that D-mannose increased the expression of OT and OTR through polarization of macrophages to the M2 type. Conclusions This is the first study to demonstrate that macrophage polarization differentially regulates the expression of OT and OTR in enteric neurons.

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The effect of macrophages polarization on the expression of oxytocin signaling system in enteric neurons

10.21203/rs.3.rs-611538/v1 ◽

2021 ◽

Author(s):

Yao Shi ◽

Shuang Li ◽

Haojie Zhang ◽

Jianchun Zhu ◽

Tongtong Che ◽

...

Keyword(s):

Enteric Neurons ◽

Signaling System ◽

M1 Macrophages ◽

Macrophages Polarization ◽

Tnf Α ◽

First Time ◽

Anti Inflammatory Cytokine ◽

Colitis Model ◽

M1 Type

Abstract Background: The aim of the current study is to investigate the effect of macrophages polarization on the expression of oxytocin (OT) and oxytocin receptor (OTR) in enteric neurons. Methods: In this study, we used a classic colitis model to observe the correlation between macrophages polarization and OT signaling system. In order to further demonstrate the effect of macrophages, we examined the expression of OT signaling system after depletion of macrophages. Results: The data showed that, in vitro, flowing macrophages polarization to M1 type by LPS, the macrophages supernatant inhibited the expression of OT and OTR in cultured enteric neurons through releasing pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α); flowing macrophages polarization to M2 type by IL4, the macrophages supernatant promoted the expression of OT and OTR in cultured enteric neurons through releasing anti-inflammatory cytokine (TGF-β). Furthermore, M1 macrophages decreased the expression of OT signaling system mainly through STAT3/NF-κB pathways in cultured enteric neurons; M2 macrophages increased expression of OT signaling system mainly through activation of Smad2/3 and inhibiting the expression of Peg3 in cultured enteric neurons. In DSS model, we demonstrated that macrophages were polarized to M1 type during the inflammatory phases, the expression of OT and OTR decreased significantly; and macrophages were polarized to M2 type during the recovery phases, the expression of OT and OTR increased significantly. At the same time, we also found that D-mannose increased the expression of OT and OTR through polarization of macrophages to M2 type. Conclusions: This is the first time to prove that the polarization of macrophages differentially regulates the expression of OT and OTR in enteric neurons.

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Abnormal Macrophage Polarization in Patients with Myelodysplastic Syndrome

Mediators of Inflammation ◽

10.1155/2021/9913382 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Gaochao Zhang ◽

Liyan Yang ◽

Yu Han ◽

Haiyue Niu ◽

Li Yan ◽

...

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndrome ◽

Macrophage Polarization ◽

Control Group ◽

M2 Macrophages ◽

M1 Macrophages ◽

Tnf Α ◽

Bone Marrow Microenvironments ◽

Medical University

Background. This study is aimed at assessing the subsets of bone marrow macrophages in patients with myelodysplastic syndrome (MDS) and exploring the role of macrophages in the pathogenesis of MDS. Methods. Thirty-eight newly diagnosed MDS patients were enrolled in the Department of Hematology of General Hospital of Tianjin Medical University from June 2015 to June 2016. Bone marrow monocytes and macrophage subsets (M1/M2) were detected in patients with MDS and normal controls by flow cytometry. M1 macrophages were cultured in vitro, and the expression of IL-1β and TNF-α mRNA was measured using real-time polymerase chain reaction. Results. Compared with the normal control group, the proportion of bone marrow monocytes was higher ( 2.11 ± 0.93 % vs. 3.66 ± 3.38 % ), and the mean fluorescence intensity of surface molecule CD14 was lower in the higher-risk (HR) MDS group ( 639.05 ± 359.78 vs. 458.26 ± 306.72 , p < 0.05 ). The ratio of M2 macrophages to monocytes was higher in patients with HR-MDS ( 1.82 ± 2.47 % vs. 3.93 ± 3.81 % , p < 0.05 ). The ratio of M1 to M2 macrophages was lower in the HR-MDS group ( 3.50 ± 3.22 vs. 1.80 ± 0.88 , p < 0.05 ). The expression of IL-1β and TNF-α mRNA in M1 macrophages was significantly lower in the MDS group ( p < 0.05 ). Conclusions. Patients with MDS had abnormal macrophage polarization, which may be involved in the alteration of bone marrow microenvironments.

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Vincristine Leads to Colonic Myenteric Neurons Injury via Stimulating M1 Macrophages Polarization

10.21203/rs.3.rs-89256/v1 ◽

2020 ◽

Author(s):

Yifei Gao ◽

Yan Tang ◽

Haojie Zhang ◽

Xili Chu ◽

Bing Yan ◽

...

Keyword(s):

Malignant Tumors ◽

Underlying Mechanism ◽

Enteric Neurons ◽

Peripheral Neurotoxicity ◽

M1 Macrophages ◽

Myenteric Neurons ◽

Macrophages Polarization ◽

Tnf Α ◽

M1 Type ◽

Proinflammatory Factors

Abstract BackgroundVincristine is widely used in treatment of various malignant tumors. The clinical application of vincristine is accompanied by peripheral neurotoxicity. The effect of vincristine on enteric neurons and the underlying mechanism are still unclear. MethodsC57BL6/J mice were systematically treated with vincristine for 10 days, and macrophages were depleted using clodronate liposomes. The colonic myenteric plexus neurons were extracted. Macrophages from different parts were extracted in an improved way.ResultsIn the current study, we demonstrated that system treatment of vincristine resulted in colonic myenteric neurons injury, proinflammatory factors increase and total gastrointestinal transport time increase. Vincristine promoted the M1-type macrophages polarization individually or in coordination with LPS and increased proinflammatory factors IL-1β, IL-6, TNF-α via increasing the phosphorylation of ERK1/2 and p38. In addition, these proinflammatory factors led to colonic myenteric neurons apoptosis targeting on SGK1-FOXO3 pathway. Importantly, macrophage depletion alleviated colonic myenteric neurons injury and the increase of proinflammatory factors caused by system treatment of vincristine.ConclusionsSystem treatment of vincristine led to colonic myenteric neurons injury via stimulating M1 macrophages polarization which was alleviated by depletion of macrophages.

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Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

Journal of Inflammation ◽

10.1186/s12950-020-00267-z ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Keizo Kohno ◽

Satomi Koya-Miyata ◽

Akira Harashima ◽

Takahiko Tsukuda ◽

Masataka Katakami ◽

...

Keyword(s):

Wound Healing ◽

Chronic Wounds ◽

Macrophage Polarization ◽

Phenotypic Switching ◽

Apoptotic Cells ◽

Phenotypic Switch ◽

Inflammatory Phase ◽

M1 Macrophage ◽

Tnf Α ◽

Anti Inflammatory

Abstract Background NK-4 has been used to promote wound healing since the early-1950s; however, the mechanism of action of NK-4 is unknown. In this study, we examined whether NK-4 exerts a regulatory effect on macrophages, which play multiple roles during wound healing from the initial inflammatory phase until the tissue regeneration phase. Results NK-4 treatment of THP-1 macrophages induced morphological features characteristic of classically-activated M1 macrophages, an inflammatory cytokine profile, and increased expression of the M1 macrophage-associated molecules CD38 and CD86. Interestingly, NK-4 augmented TNF-α production by THP-1 macrophages in combination with LPS, Pam3CSK4, or poly(I:C). Furthermore, NK-4 treatment enhanced THP-1 macrophage phagocytosis of latex beads. These results indicate that NK-4 drives macrophage polarization toward an inflammatory M1-like phenotype with increased phagocytic activity. Efferocytosis is a crucial event for resolution of the inflammatory phase in wound healing. NK-4-treated THP-1 macrophages co-cultured with apoptotic Jurkat E6.1 (Apo-J) cells switched from an M1-like phenotype to an M2-like phenotype, as seen in the inverted ratio of TNF-α to IL-10 produced in response to LPS. We identified two separate mechanisms that are involved in this phenotypic switch. First, recognition of phosphatidylserine molecules on Apo-J cells by THP-1 macrophages downregulates TNF-α production. Second, phagocytosis of Apo-J cells by THP-1 macrophages and activation of PI3K/Akt signaling pathway upregulates IL-10 production. Conclusion It is postulated that the phenotypic switch from a proinflammatory M1-like phenotype to an anti-inflammatory M2-like phenotype is dysregulated due to impaired efferocytosis of apoptotic neutrophils at the wound site. Our results demonstrate that NK-4 improves phagocytosis of apoptotic cells, suggesting its potential as a therapeutic strategy to resolve sustained inflammation in chronic wounds.

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Cervus nippon var. mantchuricus water extract treated with digestive enzymes (CE) modulates M1 macrophage polarization through TLR4/MAPK/NF-κB signaling pathways on murine macrophages

European Journal of Inflammation ◽

10.1177/20587392211000898 ◽

2021 ◽

Vol 19 ◽

pp. 205873922110008

Author(s):

Se Hyang Hong ◽

Jin Mo Ku ◽

Ye Seul Lim ◽

Hyo In Kim ◽

Yong Cheol Shin ◽

...

Keyword(s):

Digestive Enzymes ◽

Macrophage Polarization ◽

Water Extract ◽

Cervus Nippon ◽

No Production ◽

M1 Macrophages ◽

Murine Macrophages ◽

M1 Macrophage ◽

Tnf Α ◽

Cytokine Levels

The objective of this study was to investigate the effects of Cervus nippon var. mantchuricus water extract treated with digestive enzymes (CE) on the promotion of M1 macrophage polarization in murine macrophages. Macrophages polarize either to one phenotype after stimulation with LPS or IFN-γ or to an alternatively activated phenotype that is induced by IL-4 or IL-13. Cell viability of RAW264.7 cells was determined by WST-1 assay. NO production was measured by Griess assay. IL-6, IL-12, TNF-α, and iNOS mRNA levels were measured by RT-PCR. IL-6, IL-12, and IL-10 cytokine levels were determined by ELISA. TLR4/MAPK/NF-κB signaling in RAW264.7 cells was evaluated by western blotting. The level of NF-κB was determined by immunoblotting. CE induced the differentiation of M1 macrophages. CE promoted M1 macrophages to elevate NO production and cytokine levels. CE-stimulated M1 macrophages had enhanced IL-6, IL-12, and TNF-α. CE promoted M1 macrophages to activate TLR4/MAPK/NF-κB phosphorylation. M2 markers were downregulated, while M1 markers were upregulated in murine macrophages by CE. Consequently, CE has immunomodulatory activity and can be used to promote M1 macrophage polarization through the TLR4/MAPK/NF-κB signaling pathways.

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B cell activating factor regulates periodontitis development by suppressing inflammatory responses in macrophages

BMC Oral Health ◽

10.1186/s12903-021-01788-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Lixia Wang ◽

Tianyi Zhang ◽

Zheng Zhang ◽

Zihan Wang ◽

Yu-Jie Zhou ◽

...

Keyword(s):

B Cell ◽

Alveolar Bone ◽

Macrophage Polarization ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Rt Pcr ◽

B Cell Activating Factor ◽

Tnf Α

Abstract Background B cell activating factor (BAFF) is a member of the tumor necrosis factor (TNF) superfamily with immunomodulatory effects on both innate and adaptive immune responses. Periodontitis is an inflammatory disease characterized by periodontal soft tissue inflammation and the progressive loss of periodontal ligament and alveolar bone. Macrophages are closely related to periodontitis progression. However, the role of BAFF in periodontitis development and macrophage polarization and the underlying mechanism remain unknown. Methods In vivo, a ligation-induced mouse model of periodontitis for BAFF blockade was established to investigate the expression of inducible nitric oxide synthase (iNOS) through real-time PCR (RT-PCR) and immunohistochemistry. In addition, the level of TNF-α in the periodontium, the number of osteoclasts, and alveolar bone resorption were observed. In vitro, RAW 264.7 macrophage cells were treated with 100 ng/mL Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS) in either the presence or absence of 50 nM small interfering RNA (siRNA) targeting BAFF, followed by further incubation for 24 h. These cells and supernatants were collected and stored for RT-PCR, enzyme-linked immunosorbent assay, western blotting and immunofluorescence microscopy. Results In vivo, BAFF blockade decreased the levels of TNF-α in the periodontium in a ligature-induced mouse periodontitis model. Reduced osteoclast formation and lower alveolar bone loss were also observed. In addition, BAFF blockade was related to the expression of polarization signature molecules in macrophages. In vitro, BAFF knockdown notably suppressed the production of TNF-α in RAW 264.7 cells stimulated by P. gingivalis LPS. Moreover, BAFF knockdown attenuated the polarization of RAW 264.7 cells into classically activated macrophages (M1), with reduced expression of iNOS. Conclusions Based on our limited evidence, we showed BAFF blockade exhibits potent anti-inflammatory properties in mice experimental periodontitis in vivo and in P. gingivalis LPS-treated RAW 264.7 cells in vitro, and macrophage polarization may be responsible for this effect.

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Glycoproteins From Rabdosia japonica var. glaucocalyx Regulate Macrophage Polarization and Alleviate Lipopolysaccharide-Induced Acute Lung Injury in Mice via TLR4/NF-κB Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.693298 ◽

2021 ◽

Vol 12 ◽

Author(s):

An-qi Ren ◽

Hui-jun Wang ◽

Hai-yan Zhu ◽

Guan Ye ◽

Kun Li ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Western Blot ◽

Mononuclear Cells ◽

Macrophage Polarization ◽

Enzyme Linked Immunosorbent Assay ◽

Protective Effects ◽

Proinflammatory Mediators ◽

Tnf Α

Background and Aims:Rabdosia japonica var. glaucocalyx is a traditional Chinese medicine (TCM) for various inflammatory diseases. This present work aimed to investigate the protective effects of R. japonica var. glaucocalyx glycoproteins on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the potential mechanism.Methods: Glycoproteins (XPS) were isolated from R. japonica var. glaucocalyx, and homogeneous glycoprotein (XPS5-1) was purified from XPS. ANA-1 cells were used to observe the effect of glycoproteins on the secretion of inflammatory mediators by enzyme-linked immunosorbent assay (ELISA). Flow cytometry assay, immunofluorescence assay, and Western blot analysis were performed to detect macrophage polarization in vitro. The ALI model was induced by LPS via intratracheal instillation, and XPS (20, 40, and 80 mg/kg) was administered intragastrically 2 h later. The mechanisms of XPS against ALI were investigated by Western blot, ELISA, and immunohistochemistry.Results:In vitro, XPS and XPS5-1 downregulated LPS-induced proinflammatory mediators production including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and nitric oxide (NO) and upregulated LPS-induced IL-10 secretion. The LPS-stimulated macrophage polarization was also modulated from M1 to M2. In vivo, XPS maintained pulmonary histology with significantly reducing protein concentration and numbers of mononuclear cells in bronchoalveolar lavage fluid (BALF). The level of IL-10 in BALF was upregulated by XPS treatment. The level of cytokines including TNF-α, IL-1β, and IL-6 was downregulated. XPS also decreased infiltration of macrophages and polymorphonuclear leukocytes (PMNs) in lung. XPS suppressed the expression of key proteins in the TLR4/NF-κB signal pathway.Conclusion: XPS was demonstrated to be a potential agent for treating ALI. Our findings might provide evidence supporting the traditional application of R. japonica var. glaucocalyx in inflammation-linked diseases.

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Receptor-Interacting Protein Kinase 3 Inhibition Prevents Cadmium-Mediated Macrophage Polarization and Subsequent Atherosclerosis via Maintaining Mitochondrial Homeostasis

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.737652 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jiexin Zhang ◽

Weijing Feng ◽

Minghui Li ◽

Peier Chen ◽

Xiaodong Ning ◽

...

Keyword(s):

Protein Kinase ◽

Macrophage Polarization ◽

Mitochondrial Fission ◽

Underlying Mechanism ◽

Interacting Protein ◽

Mitochondrial Homeostasis ◽

Cd Exposure ◽

M1 Type

Chronic cadmium (Cd) exposure contributes to the progression of cardiovascular disease (CVD), especially atherosclerosis (AS), but the underlying mechanism is unclear. Since mitochondrial homeostasis is emerging as a core player in the development of CVD, it might serve as a potential mechanism linking Cd exposure and AS. In this study, we aimed to investigate Cd-mediated AS through macrophage polarization and know the mechanisms of Cd-caused mitochondrial homeostasis imbalance. In vitro, flow cytometry shows that Cd exposure promotes M1-type polarization of macrophages, manifested as the increasing expressions of nuclear Factor kappa-light-chain-enhancer of activated B (NF-kB) and NLR family pyrin domain containing 3 (NLRP3). Mitochondrial homeostasis tests revealed that decreasing mitochondrial membrane potential and mitophage, increasing the mitochondrial superoxide (mROS), and mitochondrial fission are involved in the Cd-induced macrophage polarization. The upregulated expressions of receptor-interacting protein kinase 3 (RIPK3) and pseudokinase-mixed lineage kinase domain-like protein (p-MLKL) were observed. Knocking out RIPK3, followed by decreasing the expression of p-MLKL, improves the mitochondrial homeostasis imbalance which effectively reverses macrophage polarization. In vivo, the oil red O staining showed that Cd with higher blood significantly aggravates AS. Besides, M1-type polarization of macrophages and mitochondrial homeostasis imbalance were observed in the aortic roots of the mice through immunofluorescence and western blot. Knocking out RIPK3 restored the changes above. Finally, the administered N-acetyl cysteine (NAC) or mitochondrial division inhibitor-1 (Mdivi-1), which decreased the mROS or mitochondrial fission, inhibited the expressions of RIPK3 and p-MLKL, attenuating AS and macrophage M1-type polarization in the Cd-treated group. Consequently, the Cd exposure activated the RIPK3 pathway and impaired the mitochondrial homeostasis, resulting in pro-inflammatory macrophage polarization and subsequent AS. Knocking out RIPK3 provided a potential therapeutic target for Cd-caused macrophage polarization and subsequent AS.

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Effect of silicon-doped calcium phosphate cement on angiogenesis based on controlled macrophage polarization

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmab121 ◽

2021 ◽

Author(s):

Soomin Lee ◽

Zheng Li ◽

Dehua Meng ◽

Qinming Fei ◽

Libo Jiang ◽

...

Keyword(s):

Calcium Phosphate ◽

Calcium Phosphate Cement ◽

Bone Repair ◽

Macrophage Polarization ◽

Calvarial Bone ◽

Inflammatory Phase ◽

Endothelial Proliferation ◽

Silicon Doped

Abstract Vascularization is an important early indicator of osteogenesis involving biomaterials. Bone repair and new bone formation are associated with extensive neovascularization. Silicon-based biomaterials have attracted widespread attention due to their rapid vascularization. Although calcium phosphate cement (CPC) is a mature substitute for bone, the application of CPC is limited by its slow degradation and insufficient promotion of neovascularization. Calcium silicate (CS) has been shown to stimulate vascular endothelial proliferation. Thus, CS may be added to CPC (CPC–CS) to improve the biocompatibility and neovascularization of CPC. In the early phase of bone repair (the inflammatory phase), macrophages accumulate around the biomaterial and exert both anti- and pro-inflammatory effects. However, the effect of CPC–CS on macrophage polarization is not known, and it is not clear whether the effect on neovascularization is mediated through macrophage polarization. In the present study, we explored whether silicon-mediated macrophage polarization contributes to vascularization by evaluating the CPC–CS-mediated changes in the immuno-environment under different silicate ion contents both in vivo and in vitro. We found that the silicon released from CPC–CS can promote macrophage polarization into the M2 phenotype and rapid endothelial neovascularization during bone repair. Dramatic neovascularization and osteogenesis were observed in mouse calvarial bone defects implanted with CPC–CS containing 60% CS. These findings suggest that CPC–CS is a novel biomaterial that can modulate immune response, promote endothelial proliferation, and facilitate neovascularization and osteogenesis. Thus, CPC–CS shows potential as a bone substitute material.

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Luteolin Regulates the Differentiation of Regulatory T Cells and Activates IL-10-Dependent Macrophage Polarization against Acute Lung Injury

Journal of Immunology Research ◽

10.1155/2021/8883962 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Ke Xie ◽

Yu-sen Chai ◽

Shi-hui Lin ◽

Fang Xu ◽

Chuan-jiang Wang

Keyword(s):

T Cells ◽

Acute Lung Injury ◽

Lung Injury ◽

Mouse Models ◽

Mononuclear Cells ◽

Macrophage Polarization ◽

M2 Macrophages ◽

M1 Macrophages ◽

Treg Differentiation

Objectives. Inflammatory disease characterized by clinical destructive respiratory disorder is called acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Studies have shown that luteolin exerts anti-inflammatory effects by increasing regulatory T cells (Tregs). In this study, we aimed to determine the effects of luteolin on ALI/ARDS and Treg differentiation. Methods. In this paper, we used cecal ligation puncture (CLP) to generate an ALI mouse model to determine the effects of luteolin on ALI/ARDS. Lung tissues were stained for interleukin- (IL-) 17A and myeloperoxidase (MPO) by immunohistochemical analysis. The levels of Treg-related cytokines in serum and bronchoalveolar lavage fluid (BALF) of mice were detected. The protein levels of NF-κB p65 in lung tissues were measured. Macrophage phenotypes in lung tissues were measured using immunofluorescence. The proportion of Tregs in splenic mononuclear cells and peripheral blood mononuclear cells (PBMCs) was quantified. Furthermore, in vitro, we evaluated the effects of luteolin on Treg differentiation, and the effects of IL-10 immune regulation on macrophage polarization were examined. Results. Luteolin alleviated lung injury and suppressed uncontrolled inflammation and downregulated IL-17A, MPO, and NF-κB in the lungs of CLP-induced mouse models. At this time, luteolin upregulated the level of IL-10 in serum and BALF and the frequency of CD4+CD25+FOXP3+ Tregs in PBMCs and splenic mononuclear cells of CLP mice. Luteolin treatment decreased the proportion of M1 macrophages and increased the proportion of M2 macrophages in lungs of CLP-induced mouse models. In vitro, administration of luteolin significantly induced Treg differentiation, and IL-10 promoted the polarization of M2 macrophages but reduced the polarization of M1 macrophages. Conclusions. Luteolin alleviated lung injury and suppressed uncontrolled inflammation by inducing the differentiation of CD4+CD25+FOXP3+ Tregs and upregulating the expression of IL-10. Furthermore, the anti-inflammatory cytokine IL-10 promoted polarization of M2 macrophages in vitro. Luteolin-induced Treg differentiation from naïve CD4+ T cells may be a potential mechanism for regulating IL-10 production.

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