Low-Dose Decitabine Could Improve the Imbalance of M1/M2 Ratio in Immune Thrombocytopenia

Abstract Background Primary immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disease characterized by increased immune-mediated platelet destruction and insufficient platelet production. As the impaired balance of M1 macrophage and M2 macrophage subsets increases platelet destruction, the M1/M2 ratio has become the focus of attention. The demethylating agent, decitabine (DAC) has been successfully used in the treatment of myelodysplastic syndrome with a moderate response in thrombocytopenia. Interestingly, at low doses, DAC induces megakaryocyte differentiation and maturation in vitro via inducing hypomethylation, thus having the potential to promote platelet release in ITP patients. In addition, several reports suggest that DAC can promote the polarization of macrophages to M2 macrophages. Therefore, we hypothesized that low dose of DAC treatment could lead to shrinkage of platelet destruction in murine model of ITP via promoting the M2 macrophage polarization. Methods Platelets isolated from Wistar rats were transferred into CBA/Ht mice via intraperitoneal injection weekly to induce a marine model of primary ITP. Starting on day 8, ITP mice were treated with low-dose DAC (0.25 mg/kg/d, n = 8) or PBS (n = 8) for two consecutive weeks intraperitoneally. Platelet counts were recorded every three days. The spleens were removed at day 10, from which M1 macrophages (F4/80+ CD11c+) and M2 macrophages (F4/80+ CD206+) were identified by flow cytometry analysis and immunofluorescence. Results The platelet levels in ITP group began to descend sharply at the second week after transferring platelets when compared with the control group (735.0 ± 25.2 × 109vs. 390.3 ± 70.0 × 109, p < 0.05). Mice in DAC-treated group recovered from thrombocytopenia by day 10 (713.8 ± 29.1 × 109vs. 311.0 ± 4.5 × 109, p < 0.001). In the following days, it still showed significantly higher level of platelet in DAC-treated group than ITP group despite the trend to decline. Comparing with the ITP group, immunofluorescence revealed that spleen samples showed stronger M2 expression pattern in DAC group, and the ratio of M1/M2 declined regardless of the fact that both the percentage of M1 macrophage and M2 macrophage was increased when DAC was applied. Conclusions Low dose DAC can promote the polarization of both M1 and M2 macrophage, especially M2 macrophage, thus reversing the unbalanced M1/M2 ratio in ITP group. Further studies are required to investigate the mechanism underlies the specialized polarization of macrophages. Disclosures No relevant conflicts of interest to declare.

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Genetic deficiency of Phactr1 promotes atherosclerosis development via facilitating M1 macrophage polarization and foam cell formation

Clinical Science ◽

10.1042/cs20191241 ◽

2020 ◽

Vol 134 (17) ◽

pp. 2353-2368 ◽

Cited By ~ 2

Author(s):

Te Li ◽

Lijuan Ding ◽

Yonggang Wang ◽

Ou Yang ◽

Shudong Wang ◽

...

Keyword(s):

Knockout Mice ◽

Foam Cell ◽

Macrophage Polarization ◽

Cell Formation ◽

Plaque Burden ◽

Foam Cell Formation ◽

Control Group ◽

M2 Macrophage ◽

Coronary Syndrome ◽

M1 Macrophage

Abstract Genetic variants in phosphatase and actin regulator-1 (Phactr1) are reported to be associated with arteriosclerotic cardiovascular disease (ASCVD). However, the function of Phactr1 in atherosclerosis remains unclear. Patients with acute coronary syndrome (ACS) who underwent coronary angiography and optical coherence tomography (OCT) were enrolled and divided into non-ST segment elevation (NST-ACS) group and ST-ACS group. The expression of Phactr1 on monocytes was higher in NST-ACS and ST-ACS groups as compared with control group. Furthermore, NST-ACS patients who have more vulnerable features including thin-cap fibroatheroma (TCFA) and large lipid area showed higher levels of Phactr1 on monocytes than those with stable plaques. Through mouse models of atherosclerosis, Phactr1−/−Apoe−/− mice (double knockout mice, DKO) developed more severe atherosclerotic plaques, recruiting more macrophages into subendothelium and having elevated levels of proinflammatory cytokines in plaques. Similarly, Apoe knockout mice (Apoe−/−) receiving DKO bone marrow (BM) exhibited elevated plaque burden compared with Apoe−/− mice receiving Apoe−/− BM, indicating the protective effect of Phactr1 in hematopoietic cells. We found that depletion of Phactr1 in BM-derived macrophages (BMDMs) tended to differentiate into M1 phenotype, produced more proatherogenic cytokines and eventually converted into foam cells driven by oxidized low-density lipoprotein (ox-LDL). Mechanistically, Phactr1 activated CREB signaling via directly binding to CREB, up-regulating CREB phosphorylation and inducing KLF4 expression. Finally, overexpression of KLF4 partly rescued the excessive inflammation response and foam cell formation induced by deficiency of Phactr1. In conclusion, our study demonstrates that elevated Phactr1 in monocytes is a promising biomarker for vulnerable plaques, while increased Phactr1 attenuates atherosclerotic development via activation of CREB and M2 macrophage differentiation.

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Effect of Platelet-Rich Plasma on M1/M2 Macrophage Polarization

International Journal of Molecular Sciences ◽

10.3390/ijms22052336 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2336

Author(s):

Ryoka Uchiyama ◽

Eriko Toyoda ◽

Miki Maehara ◽

Shiho Wasai ◽

Haruka Omura ◽

...

Keyword(s):

Culture Media ◽

Platelet Rich Plasma ◽

Point Of Care ◽

Macrophage Polarization ◽

Osteoarthritis Of The Knee ◽

M2 Macrophage ◽

Related Factors ◽

Humoral Factors ◽

M1 Macrophage ◽

M2 Macrophage Polarization

Osteoarthritis of the knee (OAK) is a chronic degenerative disease and progresses with an imbalance of cytokines and macrophages in the joint. Studies regarding the use of platelet-rich plasma (PRP) as a point-of-care treatment for OAK have reported on its effect on tissue repair and suppression of inflammation but few have reported on its effect on macrophages and macrophage polarization. Based on our clinical experience with two types of PRP kits Cellaid Serum Collection Set P type kit (leukocyte-poor-PRP) and an Autologous Protein Solution kit (APS leukocyte-rich-PRP), we investigated the concentrations of humoral factors in PRPs prepared from the two kits and the effect of humoral factors on macrophage phenotypes. We found that the concentrations of cell components and humoral factors differed between PRPs purified using the two kits; APS had a higher concentration of M1 and M2 macrophage related factors. The addition of PRP supernatants to the culture media of monocyte-derived macrophages and M1 polarized macrophages revealed that PRPs suppressed M1 macrophage polarization and promoted M2 macrophage polarization. This research is the first to report the effect of PRPs purified using commercial kits on macrophage polarization.

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Effects of Rapamycin Combined with Low Dose Prednisone in Patients with Chronic Immune Thrombocytopenia

Clinical and Developmental Immunology ◽

10.1155/2013/548085 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 15

Author(s):

Jiaming Li ◽

Zhaoyue Wang ◽

Lan Dai ◽

Lijuan Cao ◽

Jian Su ◽

...

Keyword(s):

Immune Thrombocytopenia ◽

Low Dose ◽

Group Versus ◽

Treg Cells ◽

Significant Rise ◽

Control Group ◽

Foxp3 Mrna ◽

Experimental Group ◽

Dose Prednisone ◽

Chronic Immune Thrombocytopenia

We conducted this randomized trial to investigate the efficacy and safety of rapamycin treatment in adults with chronic immune thrombocytopenia (ITP). Eighty-eight patients were separated into the control (cyclosporine A plus prednisone) and experimental (rapamycin plus prednisone) groups. The CD4+CD25+CD127lowregulatory T (Treg) cells level, Foxp3 mRNA expression, and the relevant cytokines levels were measured before and after treatment. The overall response (OR) was similar in both groups (experimental group versus control group: 58% versus 62%,P=0.70). However, sustained response (SR) was more pronounced in the experimental group than in the control group (68% versus 39%,P<0.05). Both groups showed similar incidence of adverse events (7% versus 11%,P=0.51). As expected, the low pretreatment baseline level of Treg cells was seen in all patients (P<0.001); however, the experimental group experienced a significant rise in Treg cell level, and there was a strong correlation between the levels of Treg cells and TGF-beta after the treatment. In addition, the upregulation maintained a stable level during the follow-up phase. Thus, rapamycin plus low dose prednisone could provide a new promising option for therapy of ITP.

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847 Inflammasome activation in M2 macrophage restrain the immune suppressive function

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0847 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A900-A900

Author(s):

Ronghua Zhang ◽

Tienan Wang ◽

Qing Lin

Keyword(s):

T Cell ◽

T Cell Activation ◽

Culture System ◽

Cell Activation ◽

Macrophage Polarization ◽

Inflammasome Activation ◽

M2 Macrophage ◽

M1 Macrophage ◽

Suppressive Phenotype

BackgroundMacrophage is an important component in tumor microenvironment (TME) and plays multiple roles in tumor initiation, progression and metastases. In response to various stimuli within TME, macrophage exhibits high level of functional heterogeneity. There are two distinct groups of macrophages: M1 macrophage exhibits pro-inflammatory phenotype with high levels of TNF-a, IL-6, and IL-1ß, while M2 macrophage displays immune suppressive phenotype with high levels of anti-inflammatory cytokines such as IL-10 and TGF-ß. In response to the M2 cytokines, myeloid cells within the TME further acquire higher expression of PD-L1 and thus inactivate T cells. M2 cytokines can also directly inhibit T cell activation. As a result, re-polarizing M2 macrophages becomes a key concept for cancer immunotherapy. The NLRP3 inflammasome is acquired by macrophages to fight against endogenous danger signals. Macrophage NLRP3 activation has been observed in several tumor models, but the function of NLRP3 on macrophage polarity remains controversial. Inflammasome activation with IL-1ß/IL-18 secretion was reported to promote M1 polarization. However, NLRP3 activation was also reported to promote M2 polarity through up-regulation of IL4 in asthma modelMethodsHere, we have established an in vitro human macrophage NLRP3 activation system (figure 1), coupled with M2 macrophage polarization assay, to dissect the role of NLRP3 in macrophage phenotype.ResultsOur results indicate that NLRP3 activation restrained M2 phenotype and further enhanced T cell activation in an M2/T cell co-culture system (figure 2).Abstract 847 Figure 1Inflammasome activation polarize M2 macrophage intUse LPS/ATP to stimulate NLRP3 in M2 macrophage and demonstrate NLRP3 activation could reduce CD163 and increase CD86Abstract 847 Figure 2Inflammasome in M2 rescue T cell activationestablish M2/T co-culture system in vitro to demonstrate M2 could suppress T activation while Inflammatory M2 could partial rescue the suppressive phenotypeConclusionsInflammasome could be the potential target for cancer by modulating T cell activation through macrophage polarization regulation

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Macrophage Polarization in the Skin Lesion Caused by Neotropical Species of Leishmania sp

Journal of Immunology Research ◽

10.1155/2021/5596876 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Carmen M. Sandoval Pacheco ◽

Gabriela V. Araujo Flores ◽

Kadir Gonzalez ◽

Claudia M. de Castro Gomes ◽

Luiz F. D. Passero ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Macrophage Polarization ◽

Leishmania Species ◽

Skin Lesions ◽

Host Cells ◽

M2 Macrophage ◽

M2 Macrophages ◽

Intracellular Parasites ◽

Skin Biopsies ◽

Acquired Immune Responses

Macrophages play important roles in the innate and acquired immune responses against Leishmania parasites. Depending on the subset and activation status, macrophages may eliminate intracellular parasites; however, these host cells also can offer a safe environment for Leishmania replication. In this sense, the fate of the parasite may be influenced by the phenotype of the infected macrophage, linked to the subtype of classically activated (M1) or alternatively activated (M2) macrophages. In the present study, M1 and M2 macrophage subsets were analyzed by double-staining immunohistochemistry in skin biopsies from patients with American cutaneous leishmaniasis (ACL) caused by L. (L.) amazonensis, L. (V.) braziliensis, L. (V.) panamensis ,and L. (L.) infantum chagasi. High number of M1 macrophages was detected in nonulcerated cutaneous leishmaniasis (NUCL) caused by L. (L.) infantum chagasi ( M 1 = 112 ± 12 , M 2 = 43 ± 12 cells/mm2). On the other side, high density of M2 macrophages was observed in the skin lesions of patients with anergic diffuse cutaneous leishmaniasis (ADCL) ( M 1 = 195 ± 25 , M 2 = 616 ± 114 ), followed by cases of localized cutaneous leishmaniasis (LCL) caused by L. (L.) amazonensis ( M 1 = 97 ± 24 , M 2 = 219 ± 29 ), L. (V.) panamensis ( M 1 = 71 ± 14 , M 2 = 164 ± 14 ), and L. (V.) braziliensis ( M 1 = 50 ± 13 , M 2 = 53 ± 10 ); however, low density of M2 macrophages was observed in NUCL. The data presented herein show the polarization of macrophages in skin lesions caused by different Leishmania species that may be related with the outcome of the disease.

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The effect of the WKYMVm peptide on promoting mBMSC secretion of exosomes to induce M2 macrophage polarization through the FPR2 pathway

Journal of Orthopaedic Surgery and Research ◽

10.1186/s13018-021-02321-9 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Wenbo Zhao ◽

Junxian Hu ◽

Qingyi He

Keyword(s):

Western Blotting ◽

Macrophage Polarization ◽

Bone Defects ◽

The Other ◽

Formyl Peptide Receptor ◽

Cell Counting ◽

M2 Macrophage ◽

M2 Macrophages ◽

Lysosomal Activity ◽

M2 Macrophage Polarization

Abstract Background When multicystic vesicles (precursors of exosomes) are formed in cells, there are two results. One is decomposition by lysosomes, and the other is the generation of exosomes that are transported out through the transmembrane. On the other hand, M2 macrophages promote the formation of local vascularization and provide necessary support for the repair of bone defects. To provide a new idea for the treatment of bone defects, the purpose of our study was to investigate the effect of WKYMVm (Trp-Lys-Tyr-Met-Val-D-Met-NH2) peptide on the secretion of exosomes from murine bone marrow-derived MSCs (mBMSCs) and the effect of exosomes on the polarization of M2 macrophages. Methods The WKYMVm peptide was used to activate the formyl peptide receptor 2 (FPR2) pathway in mBMSCs. First, we used Cell Counting Kit-8 (CCK-8) to detect the cytotoxic effect of WKYMVm peptide on mBMSCs. Second, we used western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) to detect the expression of interferon stimulated gene 15 (ISG15) and transcription factor EB (TFEB) in mBMSCs. Then, we detected lysosomal activity using a lysozyme activity assay kit. Third, we used an exosome extraction kit and western blotting to detect the content of exosomes secreted by mBMSCs. Fourth, we used immunofluorescence and western blotting to count the number of polarized M2 macrophages. Finally, we used an inhibitor to block miRNA-146 in exosomes secreted by mBMSCs and counted the number of polarized M2 macrophages. Results We first found that the WKYMVm peptide had no toxic effect on mBMSCs at a concentration of 1 μmol/L. Second, we found that when the FPR2 pathway was activated by the WKYMVm peptide in mBMSCs, ISG15 and TFEB expression was decreased, leading to increased secretion of exosomes. We also found that lysosomal activity was decreased when the FPR2 pathway was activated by the WKYMVm peptide in mBMSCs. Third, we demonstrated that exosomes secreted by mBMSCs promote the polarization of M2 macrophages. Moreover, all these effects can be blocked by the WRWWWW (WRW4, H-Trp-Arg-Trp-Trp-Trp-Trp-OH) peptide, an inhibitor of the FPR2 pathway. Finally, we confirmed the effect of miRNA-146 in exosomes secreted by mBMSCs on promoting the polarization of M2 macrophages. Conclusion Our findings demonstrated the potential value of the WKYMVm peptide in promoting the secretion of exosomes by mBMSCs and eventually leading to M2 macrophage polarization. We believe that our study could provide a research basis for the clinical treatment of bone defects.

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Tendon-to-Bone Healing in a Rat Extra-articular Bone Tunnel Model: A Comparison of Fresh Autologous Bone Marrow and Bone Marrow–Derived Mesenchymal Stem Cells

The American Journal of Sports Medicine ◽

10.1177/0363546519862284 ◽

2019 ◽

Vol 47 (11) ◽

pp. 2729-2736

Author(s):

Jun Lu ◽

Connie S. Chamberlain ◽

Ming-liang Ji ◽

Erin E. Saether ◽

Ellen M. Leiferman ◽

...

Keyword(s):

Bone Marrow ◽

Bone Healing ◽

Macrophage Polarization ◽

Group Versus ◽

Autologous Bone Marrow ◽

Bone Tunnel ◽

Control Group ◽

M2 Macrophage ◽

Bone Interface ◽

Autologous Bone

Background: Despite widespread acceptance of fresh autologous bone marrow (BM) for use in clinical practice, limited information exists to analyze if tendon-to-bone healing could be accelerated with local use of fresh autologous BM. Purpose: To investigate the effect of fresh autologous BM on tendon-to-bone healing with a novel rat model. Study Design: Controlled laboratory study. Methods: An extra-articular bone tunnel was created and filled with an autologous tendon graft in skeletally mature Sprague-Dawley rats (N = 60). They were then randomly divided into 3 groups: BM group (injection of fresh autologous BM into the tendon-bone interface, n = 20), BM-derived mesenchymal stem cell (BMSC) group (injection of allogenic cultured BMSCs, n = 20), and the control group (tendon-bone interface without injection of BM or BMSCs, n = 20). Biomechanical, histological, and immunohistochemical analyses were performed at 2 and 6 weeks after surgery. Results: The BM group showed a relatively well-organized and dense connective tissue interface with better orientation of collagen fibers as compared with the BMSC group. At 2 weeks, the tendon-bone interface tissue thickness of the BMSC group was 140 ± 25 μm (mean ± SEM), which was significantly greater than the BM group (58 ± 15 μm). The BM group showed fewer M1 macrophages at the tendon-bone interface at 2 and 6 weeks ( P < .001). In contrast, there were more M2 macrophages at the interface in the BM group 2 and 6 weeks postoperatively when compared with controls and the BMSC group ( P < .001). Biomechanical tests revealed significantly higher stiffness in the BM group versus the control and BMSC groups at 2 and 6 weeks after surgery ( P < .05). Load to failure showed similar trends to stiffness. Conclusion: These findings indicate that local delivery of fresh autologous BM enhances tendon-to-bone healing better than the alternative treatments in this study. This effect may be partially due to the observed modulation of inflammatory processes, especially in M2 macrophage polarization. Clinical Relevance: Fresh autologous BM could be a treatment option for this disorder.

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ILC2 Proliferated by IL-33 Stimulation Alleviates Acute Colitis in Rag1-/- Mouse through Promoting M2 Macrophage Polarization

Journal of Immunology Research ◽

10.1155/2020/5018975 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Yong You ◽

Xiaoqing Zhang ◽

Xiao Wang ◽

Dan Yue ◽

Fanxiang Meng ◽

...

Keyword(s):

Body Weight ◽

Macrophage Polarization ◽

Epithelial Barrier ◽

M2 Macrophage ◽

Surface Markers ◽

M2 Macrophages ◽

Immunological Function ◽

Innate Lymphoid Cell ◽

Acute Colitis ◽

M2 Macrophage Polarization

This study was to identify functions of ILC2, a newly found innate lymphoid cell which mainly locates in mucosa organs like lungs and intestines, in IBD. We injected rIL-33 protein to C57/BL6 mouse to explore how IL-33 induces ILC2 proliferation. The results showed that ILC2 reached a proliferation peak at day 5 and expressed multiple surface markers like CD127, C-kit, CD69, CD44, ST2, CD27, DR3, MHCII, and CD90.2. ILC2 also expressed high quantity of IL-13 and IL-5 and few IL-17A which indicates a potentially immunological function in IBD development. Afterwards, we transferred sort purified ILC2 to Rag1-/- mouse given DSS to induce acute colitis in order to explore the innate function of ILC2. Data showed that ILC2 alleviates DSS-induced acute innate colitis by repairing epithelial barrier and restore body weight. Furthermore, we found that ILC2 can cause macrophages polarizing to M2 macrophages in the gut. Therefore, we concluded that ILC2 played a therapeutic role in mouse acute colitis.

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Interleukin 26 Skews Macrophage Polarization Towards M1 Phenotype by Activating cJUN and the NF-κB Pathway

Cells ◽

10.3390/cells9040938 ◽

2020 ◽

Vol 9 (4) ◽

pp. 938

Author(s):

Yi-Hsuan Lin ◽

Yi-Hsun Wang ◽

Yi-Jen Peng ◽

Feng-Cheng Liu ◽

Gu-Jiun Lin ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Messenger Rna ◽

Molecular Mechanisms ◽

Macrophage Polarization ◽

Enzyme Linked Immunosorbent Assay ◽

M2 Macrophage ◽

Macrophage Differentiation ◽

Macrophage Cells ◽

M1 Macrophage ◽

Interleukin 26

Interleukin 26 (IL-26) is a new member of the IL-10 family that is highly expressed in rheumatoid arthritis (RA). However, the functions of IL-26 produced by macrophages in RA have not been elucidated. In the present work, we evaluated the effects and the mechanisms of IL-26 on M1 and M2 macrophage differentiation. Human or mouse macrophage cells were treated with lipopolysaccharides (LPS), interferon gamma (IFNγ), or IL-4 alone or concurrently treated with IL-26 to monitor M1 or M2 macrophage subtypes. The expression level of M1 or M2 macrophage genes was evaluated by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The molecular mechanisms of downstream signaling activation during differentiation were investigated by immunoblotting assay. Our results found that IL-26 promoted macrophage cells from CD80+ M1 macrophage differentiation, not from the CD206+ M2 phenotype. The messenger RNA of M1-type macrophage markers tumor necrosis factor alpha (TNFα) and inducible nitric oxide synthase (iNOS) was up-regulated in the IL-26-treated group. Also, the M1-related proinflammatory cytokines TNFα and IL-6 were induced after IL-26 stimulation. Interestingly, IL-10, a cytokine marker of M2 macrophage, was also elevated after IL-26 stimulation. Moreover, the M1-like macrophage stimulated by IL-26 underwent cJUN, nuclear factor kappa B (NF-κB), and signal transducer and activator of transcription 1 (STAT1) activation. Our findings suggested the role of IL-26 in synovial macrophages of active rheumatoid arthritis and provided a new insight into IL-26 as a candidate therapeutic target in rheumatoid arthritis.

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TMIC-51. GBP1 RECRUITS MACROPHAGES TO PROMOTE GLIOBLASTOMA GROWTH

Neuro-Oncology ◽

10.1093/neuonc/noz175.1085 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi259-vi259

Author(s):

Lili Chen ◽

Ming Li

Keyword(s):

Macrophage Polarization ◽

Tumor Development ◽

M2 Macrophage ◽

M2 Macrophages ◽

Orthotopic Mouse Model ◽

Ccl2 Expression ◽

Molecule Inhibitor ◽

Signaling Axis ◽

And Migration

Abstract Guanylate binding protein 1 (GBP1) is an interferon-inducible large GTPase which plays a key role in tumor development, but the molecular mechanism is poorly understood. Here we investigated whether GBP1 could influence the tumor microenvironment in glioblastoma, the most common and malignant brain tumor. We found that forced expression of GBP1 in glioblastoma cells induced macrophage polarization toward an M2 phenotype via upregulating Chemokine (C-C motif) ligand 2 (CCL2). CCL2 acted via its receptor C-C chemokine receptor 2 (CCR2) to enhance macrophage cell migration in vitro. The M2 macrophages in turn promoted glioblastoma cell proliferation and migration. The orthotopic mouse model showed that GBP1 recruited M2 macrophages into tumor to promote glioblastoma progression, and targeting CCL2/CCR2 signaling axis with a small molecule inhibitor RS504393 led to decreased macrophage attraction and M2 polarization and a significant tumor growth retardation and prolonged survival of tumor-bearing mice. Clinically, GBP1 expression positively correlated with M2 macrophage numbers and CCL2 expression in glioblastoma. Taken together, our results reveal that GBP1 modulates the tumor immune microenvironment through CCL2 induction to promote glioblastoma infiltrating growth, and targeting tumor-associated macrophages may represent a new therapeutic strategy against glioblastoma.

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