Dietary Fucose Affects Macrophage Polarization and Reproductive Performance in Mice

Intestinal mucus protects epithelial and immune cells from the gut resident microorganisms, and provides growth-promoting factors as mucus-derived O-glycans for beneficial bacteria. A lack of intestinal protective mucus results in changes in the commensal microflora composition, mucosal immune system reprogramming, and inflammation. Previous work has shown that fucose, the terminal glycan chain component of the intestinal glycoprotein Mucin2, and fucoidan polysaccharides have an anti-inflammatory effect in some mouse models of colitis. This study evaluates the effect of fucose on reproductive performance in heterozygous mutant Muc2 female mice. We found that even though Muc2+/− females are physiologically indistinguishable from C57Bl/6 mice, they have a significantly reduced reproductive performance upon dietary fucose supplementation. Metagenomic analysis reveals that the otherwise healthy wild-type siblings of Muc2−/− animals have reduced numbers of some of the intestinal commensal bacterial species, compared to C57BL/6 mice. We propose that the changes in beneficial microflora affect the immune status in Muc2+/− mice, which causes implantation impairment. In accordance with this hypothesis, we find that macrophage polarization during pregnancy is impaired in Muc2+/− females upon addition of fucose. Metabolic profiling of peritoneal macrophages from Muc2+/− females reveals their predisposition towards anaerobic glycolysis in favor of oxidative phosphorylation, compared to C57BL/6-derived cells. In vitro experiments on phagocytosis activity and mitochondrial respiration suggest that fucose affects oxidative phosphorylation in a genotype-specific manner, which might interfere with implantation depending on the initial status of macrophages. This hypothesis is further confirmed in BALB/c female mice, where fucose caused pregnancy loss and opposed implantation-associated M2 macrophage polarization. Taken together, these data suggest that intestinal microflora affects host immunity and pregnancy outcome. At the same time, dietary fucose might act as a differential regulator of macrophage polarization during implantation, depending on the immune status of the host.

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Urolithin A, a Gut Metabolite, Induces Metabolic Reprogramming of Adipose Tissue by Promoting M2 Macrophage Polarization and Mitochondrial Function (OR12-02-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz049.or12-02-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Cited By ~ 1

Author(s):

Ashley Toney ◽

Soonkyu Chung

Keyword(s):

Adipose Tissue ◽

Mitochondrial Function ◽

Macrophage Polarization ◽

Peritoneal Macrophages ◽

M2 Macrophage ◽

M2 Polarization ◽

M1 Polarization ◽

Urolithin A ◽

M2 Macrophage Polarization

Abstract Objectives Macrophage polarization into pro-inflammatory M1 status is associated with the pathologic progression of adipose remodeling, while M2 polarization is linked with the resolution of inflammation. Urolithin A (UroA) is a gut metabolite derived from ellagic acid found in berries and nuts. Emerging evidence suggests UroA exerts anti-inflammatory function, but the underlying mechanism remains unknown. This study aims to test the hypothesis that UroA attenuates adipose inflammation by promoting M2 macrophage polarization. Methods To investigate the direct role of UroA in vitro, primary bone marrow-derived macrophages (BMDM) were stimulated with LPS for M1 polarization or IL-4/IL-13 for M2 polarization. Oxygen consumption rate was determined in BMDM by Seahorse extracellular flux analyzer. The anti-inflammatory role of UroA is validated by pro-IL-1β Gaussia luciferase (iGLuc) reporter assay and IL-1β secretion in J774 macrophages. Additionally, C57BL/6 mice were fed with a HF diet for 12 weeks along with UroA administration. The M1/M2 polarization status were examined in adipose tissue macrophages (ATM) and peritoneal macrophages by qPCR and protein markers. Results UroA treatment in BMDM in vitro significantly decreased Il-1β (P < 0.001), while increasing M2 markers of Arg1, Ch313 and Mgl2 (P < 0.01). UroA treatment suppressed NLRP3 inflammasome activation in J774 macrophages by decreasing iGLuc activity and IL-1β secretion in a dose-dependent manner. In vivo, UroA administration reduced HF-induced adipocyte hypertrophy, inflammatory markers, and ATM recruitment (P < 0.01) in the adipose tissue. Consistently, UroA suppressed M1 polarization but switched to M2 polarization in peritoneal macrophages, evidenced by decreased M1 signature genes of Cd11c, Tnf-α, Il-6, and Il-1β (P < 0.01), while elevated M2 markers of Ch313 and Mgl2 (P < 0.05). Lastly, UroA not only inhibits HF-driven pathogenic remodeling of adipose tissue, but also promote mitochondrial function and biogenesis. Conclusions UroA attenuates HF-driven pathologic remodeling of adipose tissue by favoring M2 macrophage polarization and augmenting mitochondrial function. Intake of UroA-producing foods may be a promising intervention strategy to mitigate obesity-mediated chronic inflammation and metabolic dysfunction. Funding Sources United States Department of Agriculture National Institute for Food and Agriculture.

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Apoptosis inhibitor of macrophage (AIM) contributes to IL-10-induced anti-inflammatory response through inhibition of inflammasome activation

Cell Death and Disease ◽

10.1038/s41419-020-03332-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Tae-Hyun Kim ◽

Kyungwon Yang ◽

Minsuk Kim ◽

Hee-Sun Kim ◽

Jihee Lee Kang

Keyword(s):

Inflammatory Responses ◽

Macrophage Polarization ◽

Peritoneal Macrophages ◽

Inflammasome Activation ◽

M2 Macrophage ◽

Caspase 1 ◽

Apoptosis Inhibitor ◽

Apoptosis Inhibitor Of Macrophage

AbstractApoptosis inhibitor of macrophage (AIM) modulates the signaling in inflammatory responses, including infection, cancer, or other immune diseases. Recent studies suggest that like interleukin-10 (IL-10), AIM is involved in alternatively activated (M2) macrophage polarization. We aimed to understand whether and how AIM is involved in IL-10-induced inhibition of inflammasome activation and resolution of inflammation. First, we demonstrated that IL-10 induced increases in mRNA and protein expression of AIM in murine bone marrow-derived macrophages (BMDM). In addition, genetic and pharmacologic inhibition of STAT3 (signal transducer and activator of transcription 3) reduced IL-10-induced AIM expression. We also found that IL-10-induced STAT3 activity enhanced the AIM promoter activity by directly binding the promoter of the AIM gene. Additionally, reduction of LPS/adenosine triphosphate (ATP)-induced IL-1β production and caspase-1 activation by IL-10 was reversed in BMDM from AIM−/− mice. Treatment of BMDM from both wild type (WT) and IL-10−/− mice with recombinant AIM showed the inhibitory effects on IL-1β and IL-18 production and caspase-1 activation. Endogenous and exogenous AIM inhibited apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) speck formation. In LPS-induced acute peritonitis, inhibition of IL-1β and IL-18 production in peritoneal lavage fluid (PLF) and serum, reduction of caspase-1 activation in peritoneal macrophages, and reduction of numbers of neutrophils and peritoneal macrophages in PLF by administration of IL-10 were not evident in AIM−/− mice. Our in vitro and in vivo data reveal a novel role of AIM in the inhibition of inflammasome-mediated caspase-1 activation and IL-1β and IL-18 production.

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871 In vitro immunoregulatory effect from cervical cancer derived mesenchymal stromal cells over molecules expression in monocyte derived macrophage polarization

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0871 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A923-A923

Author(s):

Víctor Cortés-Morales ◽

Juan Montesinos ◽

Luis Chávez-Sánchez ◽

Sandra Espíndola-Garibay ◽

Alberto Monroy-García ◽

...

Keyword(s):

Cervical Cancer ◽

Stem Cells ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Macrophage Polarization ◽

Induction Medium ◽

M2 Macrophage ◽

List Type ◽

M2 Phenotype

BackgroundMacrophages are immunological cells that sense microenvironmental signals that may result in the polarized expression of either proinflammatory (M1) or anti-inflammatory (M2) phenotype.1 Macrophages M2 are present in tumoral microenvironment and their presence in patients with cervical cancer (CeCa) is related with less survival.2Mesenchymal Stromal Cells (MSCs) are also present in tumor microenvironment of cervical cancer (CeCa-MSC), which have shown immunoregulatory effects over CD8 T cells, decreasing their cytotoxic effect against tumoral cells.3 Interestingly, MSCs from bone marrow (BM-MSC) decrease M1 and increase M2 macrophage polarization in an in vitro coculture system.4 Macrophages and MSCs are present in microenvironment of cervical cancer, however it is unknown if MSCs play a role in macrophage polarization. In the present study, we have evaluated the immunoregulatory capacity of CeCa-MSCs to induce macrophage polarization.MethodsCD14 monocytes were isolated from peripheral blood and cultivated in the absence or presence of MSCs from BM, normal cervix (NCx) and CeCa. Two culture conditions were included, in the presence of induction medium to favors M1 (GM-CSF, LPS and IFNg) or M2 (M-CSF, IL-4 and IL-13) macrophage polarization. M1 (HLA-DR, CD80, CD86 and IFNg) or M2 (CD14, CD163, CD206, IDO and IL-10) macrophage molecular markers were evaluated by flow cytometry. Finally, we evaluated concentration of IL-10 and TNFa in conditioned medium form all coculture conditions.ResultsWe observed that CeCa-MSCs and BM-MSCs in presence of M1 induction medium, decreased M1 macrophage markers (HLA-II, CD80, CD86 and IFNg), and increase the expression of CD14 (M2 macrophage marker). Interestingly, in presence of M2 induction medium, BM-MSCs and CaCe-MSCs but not CxN-MSC increased CD163, CD206, IDO and IL-10 (M2 macrophage markers). We observed a decreased concentration of TNFa in the supernatant medium from all cocultures with MSCs, but only in presence of CeCa-MSCs, increased IL-10 concentration was detected in such cocultures.ConclusionsIn contrast to NCx-MSCs, CeCa-MSCs similarly to BM-MSCs have in vitro capacity to decrease M1 and increase M2 macrophage phenotype.AcknowledgementsAcknowledgments The authors are indebted to gratefully acknowledge to CONACYT (Grant No. 272793) and IMSS (Grant no. 1731) for support to Juan J. Montesinos research.ReferencesMartinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 2014;6-13.Petrillo M, Zannoni GF, Martinelli E, et al. Polarization of tumor-associated macrophages toward M2 phenotype correlates with poor response to chemoradiation and reduced survival in patients with locally advanced cervical cancer. PLoS One 2015;10: e0136654.Montesinos JJ, Mora-García Mde L, et al. In vitro evidence of the presence of mesenchymal stromal cells in cervical cancer and their role in protecting cancer cells from cytotoxic T cell activity. Stem Cells Dev 2013;22:2508-2519.Vasandan AB, Jahnavi S, Shashank C. Human mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE 2-dependent mechanism. Sci Rep 2016;6:38308.

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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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Biological and Inflammatory Effects of Antigen 5 from Polybia paulista (Hymenoptera, Vespidae) Venom in Mouse Intraperitoneal Macrophages

Toxins ◽

10.3390/toxins13120850 ◽

2021 ◽

Vol 13 (12) ◽

pp. 850

Author(s):

Murilo Luiz Bazon ◽

Luis Gustavo Romani Fernandes ◽

Isabela Oliveira Sandrini Assugeni ◽

Lucas Machado Pinto ◽

Patrícia Ucelli Simioni ◽

...

Keyword(s):

Peritoneal Macrophages ◽

In Vivo Studies ◽

M2 Macrophage ◽

No Production ◽

Activated Macrophages ◽

In Vitro Production ◽

Polybia Paulista ◽

Antigen 5

The social wasp Polybia paulista (Hymenoptera, Vespidae) is highly aggressive, being responsible for many medical occurrences. One of the most allergenic components of this venom is Antigen 5 (Poly p 5). The possible modulation of the in vitro immune response induced by antigen 5 from P. paulista venom, expressed recombinantly (rPoly p 5), on BALB/c mice peritoneal macrophages, activated or not with LPS, was assessed. Here, we analyzed cell viability changes, expression of the phosphorylated form of p65 NF-κB subunit, nitric oxide (NO), proinflammatory cytokines production, and co-stimulatory molecules (CD80, CD86). The results suggest that rPoly p 5 does not affect NO production nor the expression of co-stimulatory molecules in mouse peritoneal macrophages. On the other hand, rPoly p 5 induced an increase in IL-1β production in non-activated macrophages and a reduction in the production of TNF-α and MCP-1 cytokines in activated macrophages. rPoly p 5 decreased the in vitro production of the phosphorylated p65 NF-κB subunit in non-activated macrophages. These findings suggest an essential role of this allergen in the polarization of functional M2 macrophage phenotypes, when analyzed in previously activated macrophages. Further investigations, mainly in in vivo studies, should be conducted to elucidate Polybia paulista Ag5 biological role in the macrophage functional profile modulation.

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Healing of Ocular Herpetic Disease Following Treatment With an Engineered FGF-1 Is Associated With Increased Corneal Anti-Inflammatory M2 Macrophages

Frontiers in Immunology ◽

10.3389/fimmu.2021.673763 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nisha R. Dhanushkodi ◽

Ruchi Srivastava ◽

Pierre-Gregoire A. Coulon ◽

Swayam Prakash ◽

Soumyabrata Roy ◽

...

Keyword(s):

Macrophage Polarization ◽

M2 Macrophage ◽

Herpes Simplex Virus 1 ◽

Cytokines And Chemokines ◽

Latently Infected ◽

Stromal Keratitis ◽

Simplex Virus ◽

Hsv 1

Herpes simplex virus 1 (HSV-1) infects the cornea and caused blinding ocular disease. In the present study, we evaluated whether and how a novel engineered version of fibroblast growth factor-1 (FGF-1), designated as TTHX1114, would reduce the severity of HSV-1-induced and recurrent ocular herpes in the mouse model. The efficacy of TTHX1114 against corneal keratopathy was assessed in B6 mice following corneal infection with HSV-1, strain McKrae. Starting day one post infection (PI), mice received TTHX1114 for 14 days. The severity of primary stromal keratitis and blepharitis were monitored up to 28 days PI. Inflammatory cell infiltrating infected corneas were characterized up to day 21 PI. The severity of recurrent herpetic disease was quantified in latently infected B6 mice up to 30 days post-UVB corneal exposure. The effect of TTHX1114 on M1 and M2 macrophage polarization was determined in vivo in mice and in vitro on primary human monocytes-derived macrophages. Compared to HSV-1 infected non-treated mice, the infected and TTHX1114 treated mice exhibited significant reduction of primary and recurrent stromal keratitis and blepharitis, without affecting virus corneal replication. The therapeutic effect of TTHX1114 was associated with a significant decrease in the frequency of M1 macrophages infiltrating the cornea, which expressed significantly lower levels of pro-inflammatory cytokines and chemokines. This polarization toward M2 phenotype was confirmed in vitro on human primary macrophages. This pre-clinical finding suggests use of this engineered FGF-1 as a novel immunotherapeutic regimen to reduce primary and recurrent HSV-1-induced corneal disease in the clinic.

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miR-657 Promotes Macrophage Polarization toward M1 by Targeting FAM46C in Gestational Diabetes Mellitus

Mediators of Inflammation ◽

10.1155/2019/4851214 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9

Author(s):

Pingping Wang ◽

Zengfang Wang ◽

Guojie Liu ◽

Chengwen Jin ◽

Quan Zhang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Macrophage Polarization ◽

Vital Role ◽

Luciferase Reporter ◽

M2 Macrophage ◽

And Migration

MicroRNA (miRNA) has been widely suggested to play a vital role of in the pathogenesis of gestational diabetes mellitus (GDM). We have previously demonstrated that miR-657 can regulate macrophage inflammatory response in GDM. However, the role of miR-657 on M1/M2 macrophage polarization in GDM pathogenesis is not clear yet. This study is aimed at elucidating this issue and identifying novel potential GDM therapeutic targets based on miRNA network. miR-657 is found to be upregulated in placental macrophages demonstrated by real-time PCR, which can enhance macrophage proliferation and migration in vitro. Luciferase reporter assay shows the evidence that FAM46C is a target of miR-657. In addition, miR-657 can promote macrophage polarization toward the M1 phenotype by downregulating FAM46C in macrophages. The present study strongly suggests miR-657 is involved in GDM pathogenesis by regulating macrophage proliferation, migration, and polarization via targeting FAM46C. miR-657/FAM46C may serve as promising targets for GDM diagnosis and treatment.

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β-carotene Suppresses Colon Cancer by Regulating M2 Macrophages and Tumor-associated Fibroblasts in Vitro and in Vivo (P02-015-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz029.p02-015-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Yerin Kim ◽

Na Youn Lee ◽

Yoo Sun Kim ◽

Yuri Kim

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Macrophage Polarization ◽

M2 Macrophage ◽

Invasion And Migration ◽

And Migration ◽

Emt Markers ◽

Β Carotene

Abstract Objectives Tumor-associated macrophages (TAMs) and tumor-associated fibroblasts (TAFs) are consisted of tumor microenvironment (TME), which are involved in cancer progression and metastasis. Interactions within TME induce M2 macrophage phenotype, TAMs, and activate TAFs. β-carotene (BC) is a well-known antioxidant and showed protective effects on several diseases, including cancers. The object of this study is to investigate the anti-colorectal cancer (CRC) effects of BC by controlling macrophage polarization and fibroblast activation. Methods TAMs were induced by treating with phorbol-12-myristate-13-acetate (PMA) and interleukin-4 (IL-4) in U937 cells and TAFs were induced by treating with transforming growth factor-β1 (TGF-β1) in CCD-18Co cells. To understand the effect of TME on cancer cells, HCT116 colon cancer cells were co-cultured with TAM or TAF conditioned media. The effects of BC on the expressions of cancer stem cells (CSCs) markers, epithelial-mesenchymal transition (EMT) markers along with invasion and migration were investigated. To confirm these results, the azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced colitis-associated CRC mice model was used. Results BC decreased M2 macrophage polarization with activating IL-6/STAT3 signaling pathways and suppressed the expressions of fibroblast activation markers and EMT markers. In addition, BC inhibited the expressions of TME-induced CSCs markers and EMT and suppressed cell invasion and migration. Furthermore, BC supplementation suppressed tumorigenesis and the expressions of M2 macrophage-associated markers, including CD206, Arg1, and Ym-1 as well as CSCs markers in vivo. Conclusions BC suppressed CRC by regulating TAMs and TAFs in vitro and in vivo, which indicated the potential therapeutic effects of BC on inflammatory diseases. Funding Sources This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education and Brain Korea 21 Plus.

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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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Protective Role of C3aR (C3a Anaphylatoxin Receptor) Against Atherosclerosis in Atherosclerosis-Prone Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314150 ◽

2020 ◽

Vol 40 (9) ◽

pp. 2070-2083

Author(s):

Lin-Lin Wei ◽

Ning Ma ◽

Kun-Yi Wu ◽

Jia-Xing Wang ◽

Teng-Yue Diao ◽

...

Keyword(s):

Inflammatory Responses ◽

Macrophage Polarization ◽

Protective Role ◽

Plaque Burden ◽

Aortic Tissue ◽

M2 Macrophage ◽

Proinflammatory Mediators ◽

Anti Inflammatory

Objective: Emerging evidence suggests that C3aR (C3a anaphylatoxin receptor) signaling has protective roles in various inflammatory-related diseases. However, its role in atherosclerosis has been unknown. The purpose of the study was to investigate the possible protective role of C3aR in aortic atherosclerosis and explore molecular and cellular mechanisms involved in the protection. Approach and Results: C3ar −/− /Apoe −/− mice were generated by cross-breeding of atherosclerosis-prone Apoe −/− mice and C3ar −/− mice. C3ar −/− /Apoe −/− mice and Apoe −/− mice (as a control) underwent high-fat diet for 16 weeks were assessed for (1) atherosclerotic plaque burden, (2) aortic tissue inflammation, (3) recruitment of CD11b + leukocytes into atherosclerotic lesions, and (4) systemic inflammatory responses. Compared with Apoe −/− mice, C3ar −/− /Apoe −/− mice developed more severe atherosclerosis. In addition, C3ar −/− /Apoe −/− mice have increased local production of proinflammatory mediators (eg, CCL2 [chemokine (C-C motif) ligand 2], TNF [tumor necrosis factor]-α) and infiltration of monocyte/macrophage in aortic tissue, and their lesional macrophages displayed an M1-like phenotype. Local pathological changes were associated with enhanced systemic inflammatory responses (ie, elevated plasma levels of CCL2 and TNF-α, increased circulating inflammatory cells). In vitro analyses using peritoneal macrophages showed that C3a stimulation resulted in upregulation of M2-associated signaling and molecules, but suppression of M1-associated signaling and molecules, supporting the roles of C3a/C3aR axis in mediating anti-inflammatory response and promoting M2 macrophage polarization. Conclusions: Our findings demonstrate a protective role for C3aR in the development of atherosclerosis and suggest that C3aR confers the protection through C3a/C3aR axis–mediated negative regulation of proinflammatory responses and modulation of macrophage toward the anti-inflammatory phenotype.

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