Recruitment Of Monocyte-derived Macrophages Research Articles

VEGFR1 TK signaling protects the lungs against LPS-induced injury by suppressing the activity of alveolar macrophages and enhancing the anti-inflammatory function of monocyte-derived macrophages

Acute lung injury (ALI) is characterized by hyperinflammation followed by vascular leakage and respiratory failure. Vascular endothelial growth factor (VEGF)-A is critical for capillary permeability; however, the role of VEGF receptor 1 (VEGFR1) signaling in ALI progression remains unclear. Here, we show that deletion of VEGFR1 tyrosine kinase (TK) signaling in mice exacerbates lipopolysaccharide (LPS)-induced ALI as evidenced by excessive pro-inflammatory cytokine production and interleukin(IL)-1β-producing neutrophil recruitment to inflamed lung tissues. ALI development involves reduced alveolar macrophage (AM) levels and recruitment of monocyte-derived macrophages (MDMs) in a VEGFR1 TK-dependent manner. VEGFR1 TK signaling reduced pro-inflammatory cytokine levels in cultured AMs. VEGFR1 TK-expressing MDMs displayed an anti-inflammatory macrophage phenotype. Additionally, the transplantation of VEGFR1 TK-expressing bone marrow (BM)-derived macrophages into VEGFR1 TK-deficient mice reduced lung inflammation. Treatment with placental growth factor (PlGF), an agonist for VEGFR1, protected the lung against LPS-induced ALI associated with increased MDMs. These results suggest that VEGFR1 TK signaling prevents LPS-induced ALI by suppressing the pro-inflammatory activity of AMs and enhancing the anti-inflammatory function of MDMs.

Cardiac Resident Macrophages Prevent Fibrosis and Stimulate Angiogenesis.

The initial hypertrophy response to cardiac pressure overload is considered compensatory, but with sustained stress, it eventually leads to heart failure. Recently, a role for recruited macrophages in determining the transition from compensated to decompensated hypertrophy has been established. However, whether cardiac resident immune cells influence the early phase of hypertrophy development has not been established. To assess the role of cardiac immune cells in the early hypertrophy response to cardiac pressure overload induced by transverse aortic constriction (TAC). We performed cytometry by time-of-flight to determine the identity and abundance of immune cells in the heart at 1 and 4 weeks after TAC. We observed a substantial increase in cardiac macrophages 1 week after TAC. We then conducted Cite-Seq single-cell RNA sequencing of cardiac immune cells isolated from 4 sham and 6 TAC hearts. We identified 12 clusters of monocytes and macrophages, categorized as either resident or recruited macrophages, that showed remarkable changes in their abundance between sham and TAC conditions. To determine the role of cardiac resident macrophages early in the response to a hypertrophic stimulus, we used a blocking antibody against macrophage colony-stimulating factor 1 receptor (CD115). As blocking CD115 initially depletes all macrophages, we allowed the replenishment of recruited macrophages by monocytes before performing TAC. This preferential depletion of resident macrophages resulted in enhanced fibrosis and a blunted angiogenesis response to TAC. Macrophage depletion in CCR2 (C-C chemokine receptor type 2) knockout mice showed that aggravated fibrosis was primarily caused by the recruitment of monocyte-derived macrophages. Finally, 6 weeks after TAC these early events lead to depressed cardiac function and enhanced fibrosis, despite complete restoration of cardiac immune cells. Cardiac resident macrophages are a heterogeneous population of immune cells with key roles in stimulating angiogenesis and inhibiting fibrosis in response to cardiac pressure overload.

Technical advance: The use of tree shrews as a model of pulmonary fibrosis.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease with a high morbidity and mortality. Some of the mechanisms of fibrosis development have been described using rodent models; however, the relevance of findings in these animal models is difficult to assess. New innovative models are needed that closely mimic IPF disease pathology.MethodsTo overcome this unmet need of investigating IPF with a relevant model, we utilized tree shrews, which are genetically, anatomically, and metabolically similar to primates and humans. Using human antibodies and primers, we investigated the role of macrophage phenotypic switching in normal and IPF subjects and bleomycin-injured tree shrews.ResultsBronchoalveolar lavage (BAL) cells from tree shrews expressed human markers, and there was recruitment of monocyte-derived macrophages (MDMs) to the lung in IPF subjects and bleomycin-injured tree shrews. MDMs were polarized to a profibrotic phenotype in IPF and in bleomycin-injured tree shrews. Resident alveolar macrophages (RAMs) expressed proinflammatory markers regardless of bleomycin exposure. Tree shrews developed bleomycin-induced pulmonary fibrosis with architectural distortion in parenchyma and widespread collagen deposition.ConclusionThe profibrotic polarization of macrophages has been demonstrated to be present in IPF subjects and in fibrotic mice. Although the lung macrophages have long been considered to be homogeneous, recent evidence indicates that these cells are heterogeneous during multiple chronic lung diseases. Here, we show new data that indicate a critical and essential role for macrophage-fibroblast crosstalk promoting fibroblast differentiation and collagen production. in the development and progression of fibrosis. The current data strongly suggest development of therapeutics that attenuate of the profibrotic activation of MDMs may mitigate macrophage-fibroblast interaction. These observations demonstrate that tree shrews are an ideal animal model to investigate the pathogenesis of IPF as they are genetically, anatomically, and metabolically closer to humans than the more commonly used rodent models.

In This Issue

HomeCirculation ResearchVol. 127, No. 5In This Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessIn BriefPDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published13 Aug 2020https://doi.org/10.1161/RES.0000000000000431Circulation Research. 2020;127:589is related toCritical Role of Neprilysin in Kidney Angiotensin MetabolismNovel Methods for Quantification of Vasodepression and Cardioinhibition During Tilt-Induced Vasovagal SyncopeSelf-Maintenance of Cardiac Resident Reparative Macrophages Attenuates Doxorubicin-Induced Cardiomyopathy Through the SR-A1-c-Myc AxisNeprilysin in Kidney Angiotensin Metabolism (p 593)In healthy kidneys, neprilysin keeps the renin-angiotensin system in balance, say Kalternecker et al.Download figureDownload PowerPointThe renin-angiotensin system (RAS) drives vasoconstriction, increased blood pressure and sodium retention in the kidneys, mainly via the action of angiotensin II (Ang II) and its receptor (AT1R). While the system is important for normal kidney function, excessive stimulation of AT1R leads to kidney damage. Angiotensin-(1-7), by contrast, drives vasodilation, reducing blood pressure and kidney damage (a so-called alternative RAS). While boosting Ang-(1-7) to counteract Ang II may seem like a potential treatment strategy for chronic kidney disease (CKD), the situation is complicated by the fact that Ang-(1-7) can actually be derived from Ang II, as well as from other precursors, and it isn’t clear which source of Ang-(1-7) predominates in kidneys. To find out, Kaltenecker and colleagues examined the abundance and activities of RAS and alternative RAS components in healthy and diseased kidney tissue. Using Ang I or Ang II as substrates, the team showed that, in healthy kidneys, Ang-(1-7) is mainly produced from Ang I via the action of an enzyme called neprilysin. In CKD tissue, Ang-(1-7) production is reduced relative to Ang II, the team also showed. These insights into RAS control in the renal system should help guide future therapies for CKD, the authors say.Self-Renewal of Local Macrophages Attenuates DiCM (p 610)Scavenger receptor SR-A1 promotes production of protective resident macrophages in doxorubicin-damaged hearts, say Zhang et al.Download figureDownload PowerPointThe chemotherapy drug doxorubicin (DOX) is effective against many types of cancer yet is damaging to the heart. The pathogenesis of DOX-induced cardiomyopathy (DiCM) is largely unknown, but accumulating evidence suggests inflammation, specifically the accumulation of macrophages, plays a critical role. Zhang and colleagues have now investigated the origins and features of cardiac macrophages during DiCM in greater detail. In mice treated with DOX, heart macrophages increased in abundance and originated from both the proliferation of resident cells and recruitment of monocyte-derived macrophages from the circulation, the team showed. These two cell populations differed in their characteristics, with those from the blood being mainly pro-inflammatory and resident cells having a reparative phenotype. The team also found that the resident macrophages exhibited an increased production of the scavenger receptor protein SR-A1 following DOX treatment, and that this receptor promoted the proliferation of the cells. Indeed, in mice lacking SR-A1 the pathology of DiCM was exacerbated. Together the results suggest that boosting the activity of these protective resident macrophages via SR-A1 augmentation may be a route to minimizing heart damage caused by DOX.Vasodepression and Cardioinhibition in VVS (p e126)van Dijk et al examine the precise cardiovascular events that precede fainting.Download figureDownload PowerPointSome people faint at the sight of blood or needles, or because they’ve stood up quickly after sitting or lying. Such individuals, who make up approximately one third of the population, have a condition known as vasovagal syncope (VVS)—thought to be caused by sudden drops in both blood pressure and heart rate. Recent evidence suggests a more complicated pre-fainting process, however, with reports that heart volume output is also reduced and that peripheral resistance—a factor affecting blood pressure—can both rise and fall. To determine the precise order and contribution of events prior to fainting, van Dijk and colleagues continuously monitored 163 patients as they underwent a tilt-table-test—a routine method for diagnosing VVS whereby a person’s position is changed from horizontal to upright. Blood pressure, heart output (stroke volume), and heart rate were all continuously assessed while patients were videoed to determine the precise timing of syncope. From averaging the results, the team determined that the initial and predominant contributing factor to fainting is a fall in the heart’s stroke volume, itself probably a result of blood pooling in the lower limbs when the patient is tilted upright. Why such reactions occur in some people and not others, however, was not investigated. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesCritical Role of Neprilysin in Kidney Angiotensin MetabolismChristopher C. Kaltenecker, et al. Circulation Research. 2020;127:593-606Novel Methods for Quantification of Vasodepression and Cardioinhibition During Tilt-Induced Vasovagal SyncopeJ. Gert van Dijk, et al. Circulation Research. 2020;127:e126-e138Self-Maintenance of Cardiac Resident Reparative Macrophages Attenuates Doxorubicin-Induced Cardiomyopathy Through the SR-A1-c-Myc AxisHanwen Zhang, et al. Circulation Research. 2020;127:610-627 August 14, 2020Vol 127, Issue 5Article InformationMetrics Download: 194 © 2020 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000431 Originally publishedAugust 13, 2020 PDF download

From the Editor's Desk…

From the Editor's Desk…

Monocyte-Derived Macrophages Are Necessary for Beta-Adrenergic Receptor-Driven Choroidal Neovascularization Inhibition.

PurposeBeta-adrenergic receptor (AR) antagonists, like propranolol, inhibit angiogenesis in multiple ocular conditions through an unknown mechanism. We previously showed that propranolol reduces choroidal neovascularization (CNV) by decreasing interleukin-6 levels. Since macrophages are one of the central producers of interleukin-6, we examined whether macrophages are required for propranolol-driven inhibition of choroidal angiogenesis.MethodsWe tested the anti-angiogenic properties of propranolol in the choroidal sprouting assay and the laser-induced CNV model. Bone marrow-derived monocytes (BMDMs) were added to the choroidal sprouting assay and Ccr2−/− mice were subjected to laser-induced CNV. Multi-parameter flow cytometry was performed to characterize the ocular mononuclear phagocyte populations after laser injury and during propranolol treatment.ResultsPropranolol reduced choroidal angiogenesis by 41% (P < 0.001) in the choroidal sprouting assay. Similarly, propranolol decreased laser-induced CNV by 50% (P < 0.05) in female mice, with no change in males. BMDMs increased choroidal sprouting by 146% (P < 0.0001), and this effect was ablated by propranolol. Beta-AR inhibition had no effect upon laser-induced CNV area in female Ccr2−/− mice. MHCII+ and MHCII− macrophages increased 20-fold following laser treatment in wildtype mice as compared to untreated mice, and this effect was completely attenuated in lasered Ccr2−/− mice. Moreover, propranolol increased the numbers of MHCII+ and MHCII− macrophages by 1.9 (P = 0.07) and 3.1 (P < 0.05) fold in lasered female mice with no change in macrophage numbers in males.ConclusionsOur data suggest that propranolol inhibits angiogenesis through recruitment of monocyte-derived macrophages in female mice only. These data show the anti-angiogenic nature of beta-AR blocker-recruited monocyte-derived macrophages in CNV.

Quantification of Monocyte Chemotactic Activity In Vivo and Characterization of Blood Monocyte Derived Macrophages.

Tissue homeostasis and repair are critically dependent on the recruitment of monocyte-derived macrophages. Both under- and over-recruitment of monocyte-derived macrophages can impair wound healing. We showed that high fat and high sugar diets promote monocyte priming and dysfunction, converting healthy blood monocytes into a hyper chemotactic phenotype poised to differentiate into macrophages with dysregulated activation profiles and impaired phenotypic plasticity. The over-recruitment of monocyte-derived macrophages and recruitment of macrophages with dysregulated activation profiles is believed to be a major contributor to the development of chronic inflammatory diseases associated with metabolic disorders, including atherosclerosis and obesity. The goal of this protocol is to quantify the chemotactic activity of blood monocytes as a biomarker for monocyte priming and dysfunction and to characterize the macrophage phenotype blood monocytes are poised to differentiate into in these mouse models. Using single cell Western blot analysis, we show that after 24 h 33%of cells recruited into MCP-1-loaded basement membrane-derived gel plugs injected into mice are monocytes and macrophages; 58% after day 3. However, on day 5, monocyte and macrophage numbers were significantly decreased. Finally, we show that this assays also allows for the isolation of live macrophages from the surgically retrieved basement membrane-derived gel plugs, which can then be subjected to subsequent characterization by single cell Western blot analysis.

Dyslipidemic Diet-Induced Monocyte "Priming" and Dysfunction in Non-Human Primates Is Triggered by Elevated Plasma Cholesterol and Accompanied by Altered Histone Acetylation.

Monocytes and the recruitment of monocyte-derived macrophages into sites of inflammation play a key role in atherogenesis and other chronic inflammatory diseases linked to cardiometabolic syndrome and obesity. Previous studies from our group have shown that metabolic stress promotes monocyte priming, i.e., enhanced adhesion and accelerated chemotaxis of monocytes in response to chemokines, both in vitro and in dyslipidemic LDLR−/− mice. We also showed that metabolic stress-induced monocyte dysfunction is, at least to a large extent caused by the S-glutathionylation, inactivation, and subsequent degradation of mitogen-activated protein kinase phosphatase 1. Here, we analyzed the effects of a Western-style, dyslipidemic diet (DD), which was composed of high levels of saturated fat, cholesterol, and simple sugars, on monocyte (dys)function in non-human primates (NHPs). We found that similar to mice, a DD enhances monocyte chemotaxis in NHP within 4 weeks, occurring concordantly with the onset of hypercholesterolemia but prior to changes in triglycerides, blood glucose, monocytosis, or changes in monocyte subset composition. In addition, we identified transitory decreases in the acetylation of histone H3 at the lysine residues 18 and 23 in metabolically primed monocytes, and we found that monocyte priming was correlated with the acetylation of histone H3 at lysine 27 after an 8-week DD regimen. Our data show that metabolic stress promotes monocyte priming and hyper-chemotactic responses in NHP. The histone modifications accompanying monocyte priming in primates suggest a reprogramming of the epigenetic landscape, which may lead to dysregulated responses and functionalities in macrophages derived from primed monocytes that are recruited to sites of inflammation.

Choroid plexus-cerebrospinal fluid route for monocyte-derived macrophages after stroke

BackgroundChoroid plexus (CP) supports the entry of monocyte-derived macrophages (MDMs) to the central nervous system in animal models of traumatic brain injury, spinal cord injury, and Alzheimer’s disease. Whether the CP is involved in the recruitment of MDMs to the injured brain after ischemic stroke is unknown.MethodsAdult male C57BL/6 mice were subjected to focal cortical ischemia by permanent occlusion of the distal branch of the right middle cerebral artery. Choroid plexus tissues were collected and analyzed for Vcam1, Madcam1, Cx3cl1, Ccl2, Nt5e, and Ifnγ expression at different timepoints after stroke using qPCR. Changes of MDMs in CP and cerebrospinal fluid (CSF) at 1 day and 3 days after stroke were analyzed using flow cytometry. Infiltration of MDMs into CP and CSF were validated using β-actin-GFP chimeric mice and Fgd5-CreERT2 x Lox-stop-lox-Tomato mice. CD115+ monocytes were isolated using a magnetic cell separation system from bone marrow of Cx3cr1-GFP or wild-type C57BL/6 donor mice. The freshly isolated monocytes or M2-like MDMs primed in vitro with IL4 and IL13 were stereotaxically injected into the lateral ventricle of stroke-affected mice to trace for their migration into ischemic hemisphere or to assess their effect on post-stroke recovery using open field, corridor, and active avoidance behavioral tests.ResultsWe found that CP responded to cortical stroke by upregulation of gene expression for several possible mediators of MDM trafficking and, concomitantly, MDMs increased in CP and cerebrospinal fluid (CSF). We then confirmed that MDMs infiltrated from blood into CP and CSF after the insult using β-actin-GFP chimeric mice and Fgd5-CreERT2 x Lox-stop-lox-Tomato mice. When MDMs were directly administered into CSF following stroke, they homed to the ischemic hemisphere. If they had been primed in vitro prior to their administration to become M2-like macrophages, they promoted post-stroke recovery of motor and cognitive function without influencing infarct volume.ConclusionsOur findings suggest the possibility that autologous transplantation of M2-like MDMs into CSF might be developed into a new strategy for promoting recovery also in patients with stroke.

Regulation of Monocyte Adhesion and Migration by Nox4

We showed that metabolic disorders promote thiol oxidative stress in monocytes, priming monocytes for accelerated chemokine-induced recruitment, and accumulation at sites of vascular injury and the progression of atherosclerosis. The aim of this study was to identify both the source of reactive oxygen species (ROS) responsible for thiol oxidation in primed and dysfunctional monocytes and the molecular mechanisms through which ROS accelerate the migration and recruitment of monocyte-derived macrophages. We found that Nox4, a recently identified NADPH oxidase in monocytes and macrophages, localized to focal adhesions and the actin cytoskeleton, and associated with phospho-FAK, paxillin, and actin, implicating Nox4 in the regulation of monocyte adhesion and migration. We also identified Nox4 as a new, metabolic stress-inducible source of ROS that controls actin S-glutathionylation and turnover in monocytes and macrophages, providing a novel mechanistic link between Nox4-derived H2O2 and monocyte adhesion and migration. Actin associated with Nox4 was S-glutathionylated, and Nox4 association with actin was enhanced in metabolically-stressed monocytes. Metabolic stress induced Nox4 and accelerated monocyte adhesion and chemotaxis in a Nox4-dependent mechanism. In conclusion, our data suggest that monocytic Nox4 is a central regulator of actin dynamics, and induction of Nox4 is the rate-limiting step in metabolic stress-induced monocyte priming and dysfunction associated with accelerated atherosclerosis and the progression of atherosclerotic plaques.

Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-β in murine brain

Neuroinflammation is typically observed in neurodegenerative diseases such as Alzheimer’s disease, as well as after traumatic injury and pathogen infection. Resident immune cells, microglia and astrocytes, are activated and joined by blood-borne monocytes that traverse the blood–brain barrier and convert into activated macrophages. The activated cells express various cytokines, chemokines and proteolytic enzymes. To study the role of heparan sulfate proteoglycans in neuroinflammation, we employed a transgenic mouse overexpressing heparanase, an endoglucuronidase that specifically degrades heparan sulfate side chains. Neuroinflammation was induced by systemic challenge with lipopolysaccharide, or by localized cerebral microinjection of aggregated amyloid-β peptide, implicated in Alzheimer’s disease. Lipopolysaccharide-treated control mice showed massive activation of resident microglia as well as recruitment of monocyte-derived macrophages into the brain parenchyma. Microinjection of aggregated amyloid-β elicited a similar inflammatory response, albeit restricted to the injection site, which led to dispersion and clearance of the amyloid. In the heparanase-overexpressing mice, all aspects of immune cell recruitment and activation were significantly attenuated in both inflammation models, as was amyloid dispersion. Accordingly, an in vitro blood–brain barrier model constructed from heparanase-overexpressing cerebral vascular cells showed impaired transmigration of monocytes compared to a corresponding assembly of control cells. Our data indicate that intact heparan sulfate chains are required at multiple sites to mediate neuroinflammatory responses, and further point to heparanase as a modulator of this process, with potential implications for Alzheimer’s disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-012-0997-1) contains supplementary material, which is available to authorized users.

The Innate Immune Adaptor Molecule MyD88 Restricts West Nile Virus Replication and Spread in Neurons of the Central Nervous System

Type I interferons (IFN-α/β) control viral infection by triggering the expression of genes that restrict transcription, translation, replication, and assembly. Many viruses induce IFN responses after recognition by cytoplasmic or endosomal RNA sensors (RIG-I-like RNA helicases [RLR] and Toll-like receptors [TLR]), which signal through the cognate adaptor signaling molecules IPS-1, TRIF, and MyD88. Recent studies have demonstrated that IPS-1-dependent induction of IFN-α/β downstream of RLR recognition restricts West Nile virus (WNV) infection in many cell types, whereas TRIF-dependent TLR3 signaling limits WNV replication in neurons. Here, we examined the contribution of MyD88 signaling to the control of WNV by evaluating IFN induction and virus replication in genetically deficient cells and mice. MyD88(-/-) mice showed increased lethality after WNV infection and elevated viral burden primarily in the brain, even though little effect on the systemic type I IFN response was observed. Intracranial inoculation studies corroborated these findings, as WNV spread more rapidly in the central nervous system of MyD88(-/-) mice, and this phenotype preceded the recruitment of inflammatory leukocytes. In vitro, increased WNV replication was observed in MyD88(-/-) macrophages and subsets of neurons but not in myeloid dendritic cells. MyD88 had an independent effect on recruitment of monocyte-derived macrophages and T cells into the brain that was associated with blunted induction of the chemokines that attract leukocytes. Our experiments suggest that MyD88 restricts WNV by inhibiting replication in subsets of cells and modulating expression of chemokines that regulate immune cell migration into the central nervous system.

Attenuation of AD‐like neuropathology by harnessing peripheral immune cells: local elevation of IL‐10 and MMP‐9

Immunization with an altered myelin-derived peptide (MOG45D) improves recovery from acute CNS insults, partially via recruitment of monocyte-derived macrophages that locally display a regulatory activity. Here, we investigated the local alterations in the cellular and molecular immunological milieu associated with attenuation of Alzheimer's disease-like pathology following immunotherapy. We found that immunization of amyloid precursor protein/presenilin 1 double-transgenic mice with MOG45D peptide, loaded on dendritic cells, led to a substantial reduction of parenchymal and perivascular amyloid beta (Abeta)-plaque burden and soluble Abeta((1-42)) peptide levels as well as reduced astrogliosis and levels of a key glial scar protein (chondroitin sulphate proteoglycan). These changes were associated with a shift in the local innate immune response, manifested by increased Iba1+/CD45(high) macrophages that engulfed Abeta, reduced pro-inflammatory (tumor necrosis factor-alpha) and increased anti-inflammatory (interleukin-10) cytokines, as well as a significant increase in growth factors (IGF-1 and TGFbeta) in the brain. Furthermore, the levels of matrix metalloproteinase-9, an enzyme shown to degrade Abeta and is associated with glial scar formation, were significantly elevated in the brain following immunization. Altogether, these results indicate that boosting systemic immune cells leads to a local immunomodulation manifested by elevated levels of anti-inflammatory cytokines and metalloproteinases that contribute to ameliorating Alzheimer's disease pathology.

IFNγ regulates PDGF-receptor alpha expression in macrophages, THP-1 cells, and arterial smooth muscle cells

The recruitment of monocyte-derived macrophages (MDMs) and arterial smooth muscle cells (ASMCs) contributes to inflammation and development of intimal hyperplasia during atherosclerosis. Platelet-derived growth factor (PDGF) is a potent mitogen for SMC, signalling through PDGF-receptor subunits α (Rα) and β (Rβ). We have previously found that interferon gamma (IFNγ) upregulates PDGF-Rα mRNA expression in human MDM (hMDM) which causes an increased migration towards PDGF. In the present study, we found that IFNγ mediated an upregulation of PDGF-Rα mRNA also in THP-1 cells. The induction of PDGF-Rα in both hMDM and THP-1 cells was caused by STAT1 binding to the PDGF-Rα promoter. In human ASMCs, IFNγ again stimulated a transient STAT1-binding to the PDGF-Rα promoter. However, this was not followed by an upregulation of PDGF-Rα mRNA. IFNγ-stimulation resulted in augmented expression of PDGF-Rα protein in differentiated hMDM. Early hMDM only expressed an immature and not fully glycosylated form of the PDGF-Rα protein. In contrast, THP-1 cells did not synthesize PDGF-Rα protein, implying further posttranscriptional inhibition. Our results contribute to a better understanding of the complex regulation of PDGF-Rα expression and how proinflammatory factors may contribute to PDGF-related hyperplasia in vascular diseases.