Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice.
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ABSTRACT:
SUBMITTER: Channappanavar R
PROVIDER: S-EPMC4752723 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Murine cytomegalovirus (MCMV) brain infection induces a transient increase in chemokine production, which precedes the infiltration of CD3(+) lymphocytes. In this study, we hypothesized that an absence of anti-inflammatory cytokines would result in sustained proinflammatory neuroimmune responses. Direct intracerebroventricular injection of MCMV into IL-10 knockout (KO) mice produced an unexpected result: while wild-type animals controlled MCMV, the infection was lethal in IL-10 KO animals. Identical infection of IL-4 KO animals did not produce lethal disease. To further characterize the role of IL-10, infected brain tissue from both wild-type and IL-10 KO animals was assessed for cytokine and chemokine levels, as well as viral gene expression. These data show vastly elevated levels of interferon (IFN)-gamma, and the IFN-gamma-inducible chemokines CXCL9 and CXCL10, as well as IL-6 in brain homogenates obtained from IL-10 KO animals. However, MCMV viral load, glycoprotein B mRNA levels, and titers of infectious virus were similar in both IL-10 KO and wild-type animals. Separation of cells isolated from murine brain tissue into distinct populations using FACS, along with subsequent quantitative RT real-time PCR, showed that brain-infiltrating CD45(hi)/CD11b(-) and CD45(hi)/CD11b(int) were the cellular source of IL-10 in the brain. Taken together, these data demonstrate that MCMV brain infection of IL-10-deficient mice causes lethal disease, which occurs in the presence of a dysregulated IFN-gamma-mediated neuroimmune response.
| S-EPMC2134841 | biostudies-literature
Project description:Macrophages are critical components of atherosclerotic lesions and their pro- and anti-inflammatory responses influence atherogenesis. Type-I interferons (IFNs) are cytokines that play an essential role in antiviral responses and inflammatory activation and have been shown to promote atherosclerosis. Although the impact of type-I IFNs on macrophage foam cell formation is well-documented, the effect of lipid accumulation in monocytes and macrophages on type-I IFN responses remains unknown. Here we examined IFN stimulated (ISG) and non-ISG inflammatory gene expression in mouse and human macrophages that were loaded with acetylated LDL (acLDL), as a model for foam cell formation. We found that acLDL loading in mouse and human macrophages specifically suppressed expression of ISGs and IFN-β secretion, but not other pro-inflammatory genes. The down regulation of ISGs could be rescued by exogenous IFN-β supplementation. Activation of the cholesterol-sensing nuclear liver X receptor (LXR) recapitulated the cholesterol-initiated type-I IFN suppression. Additional analyses of murine in vitro and in vivo generated foam cells confirmed the suppressed IFN signaling pathways and suggest that this phenotype is mediated via down regulation of interferon regulatory factor binding at gene promoters. Finally, RNA-seq analysis of monocytes of familial hypercholesterolemia (FH) patients also showed type-I IFN suppression which was restored by lipid-lowering therapy and not present in monocytes of healthy donors. Taken together, we define type-I IFN suppression as an athero-protective characteristic of foamy macrophages. These data provide new insights into the mechanisms that control inflammatory responses in hyperlipidaemic settings and can support future therapeutic approaches focusing on reprogramming of macrophages to reduce atherosclerotic plaque progression and improve stability.
| S-EPMC8869252 | biostudies-literature
Project description:Host-defense peptides play a fundamental role in the innate immune system by modulating inflammatory responses. Previously, it was shown that the thrombin derived host-defense peptide GKY25 inhibits LPS-induced responses of monocytes and macrophages in vitro, ex vivo, and in vivo. In this study, the effect of GKY25 on the interaction of monocytes/macrophages with Gram-negative bacteria was explored. Electron microscopy analysis showed that fibrin slough from non-healing wounds, colonized with Staphylococcus aureus and Pseudomonas aeruginosa, contains C-terminal thrombin epitopes associated with these bacteria extracellularly and in phagosomes of leukocytes. Live imaging of RAW 264.7 cell cultures showed binding of GKY25 to Escherichia coli BioParticles extracellularly, and colocalization intracellularly. Although peptide binding did not alter the rate of phagocytosis, GKY25 reduced NF-?B/AP-1 activation and subsequent cytokine release in response to both heat-killed and live bacteria. Notably, preincubation of RAW 264.7 cells with peptide did increase BioParticle uptake in a dose-dependent manner. Taken together, the thrombin-derived host-defense peptide GKY25 binds to bacteria extracellularly and colocalizes with bacteria intracellularly, thereby reducing pro-inflammatory responses.
| S-EPMC5519531 | biostudies-literature
Project description:ObjectivePeripheral blood mononuclear cells (PBMCs) in systemic lupus erythematosus (SLE) patients exhibit a gene expression program (interferon [IFN] signature) that is attributed to overproduction of type I IFNs by plasmacytoid dendritic cells. Type I IFNs have been thought to play a role in the pathogenesis of SLE. This study was undertaken to examine an unexpected influence of monocyte/macrophages on the IFN signature.MethodsProinflammatory (classic) and antiinflammatory (nonclassic) monocyte/macrophages were sorted from mice and analyzed by RNA sequencing and quantitative polymerase chain reaction (qPCR). Type I IFN-?/?/? receptor (IFNAR-1) expression was determined by qPCR and flow cytometry. Macrophages were stimulated in vitro with IFN?, and pSTAT1was measured.ResultsTranscriptional profiling of peritoneal macrophages from mice with pristane-induced SLE unexpectedly indicated a strong IFN signature in classic, but not nonclassic, monocyte/macrophages exposed to the same type I IFN concentrations. Ifnar1 messenger RNA and IFNAR surface staining were higher in classic monocyte/macrophages versus nonclassic monocyte/macrophages (P < 0.0001 and P < 0.05, respectively, by Student's t-test). Nonclassic monocyte/macrophages were also relatively insensitive to IFN?-driven STAT1 phosphorylation. Humans exhibited a similar pattern: higher IFNAR expression (P < 0.0001 by Student's t-test) and IFN?-stimulated gene expression (P < 0.01 by paired Wilcoxon's rank sum test) in classic monocyte/macrophages and lower levels in nonclassic monocyte/macrophages.ConclusionThis study revealed that the relative abundance of different monocyte/macrophage subsets helps determine the magnitude of the IFN signature. Responsiveness to IFN? signaling reflects differences in IFNAR expression in classic (high IFNAR) compared to nonclassic (low IFNAR) monocyte/macrophages. Thus, the IFN signature depends on both type I IFN production and the responsiveness of monocyte/macrophages to IFNAR signaling.
| S-EPMC6935410 | biostudies-literature
Project description:Necrotizing enterocolitis (NEC) is a life-threatening, inflammatory disease affecting premature infants with intestinal necrosis, but the mechanism remains unclear. Neonatal macrophages are thought to play an important role in the pathogenesis of NEC through the production of proinflammatory cytokines. Restriction of cytokine expression in macrophages of NEC tissues may be beneficial. In adult macrophages, interfering with Rac1 has been shown to influence the expression of cytokines. Here, we investigated whether interfering with Rac1 in neonatal macrophages affects their inflammatory responses. First, we found that Rac1-activation was upregulated in the macrophages of rats with NEC model induction compared to controls. The M1 macrophages derived from human neonatal monocytes showed greater Rac1-activation than the M2 macrophages derived from the same monocytes. Inhibition of Rac1-activation by NSC23766 potently reduced the production of proinflammatory cytokines in these M1 macrophages. While neonatal monocytes differentiated into M1 macrophages in vitro, NSC23766 significantly altered cell function during the first six days of incubation with GM-CSF rather than during the subsequent stimulation phase. However, the same effect of NSC23766 was not observed in adult macrophages. Using mass spectrometry, Y-box binding protein 1 (YB1) was identified as being downregulated upon inhibition of Rac1-activation in the neonatal macrophages. Moreover, we found that inhibition of Rac1-activation shortens the poly A tail of PABPC1 mRNA, thereby reducing the translation of PABPC1 mRNA. Consequently, the downregulation of PABPC1 resulted in a reduced translation of YB1 mRNA. Furthermore, we found that TLR4 expression was downregulated in neonatal macrophages, while YB1 expression was reduced. Adding resatorvid (TLR4 signaling inhibitor) to the macrophages treated with NSC23766 did not further reduce the cytokine expression. These findings reveal a novel Rac1-mediated pathway to inhibit cytokine expression in neonatal M1 macrophages and suggest potential targets for the prevention or treatment of NEC.
| S-EPMC10514032 | biostudies-literature
Project description:Macrophages are critical components of atherosclerotic lesions and their pro- and anti-inflammatory responses influence atherogenesis. Type-I interferons (IFNs) are cytokines that play an essential role in antiviral responses and inflammatory activation and have been shown to promote atherosclerosis. Although the impact of type-I IFNs on macrophage foam cell formation is well-documented, the effect of lipid accumulation in monocytes and macrophages on type-I IFN responses remains unknown. Here we examined IFN stimulated (ISG) and non-ISG inflammatory gene expression in mouse and human macrophages that were loaded with acetylated LDL (acLDL), as a model for foam cell formation. We found that acLDL loading in mouse and human macrophages specifically suppressed expression of ISGs and IFN-β secretion, but not other pro-inflammatory genes. The downregulation of ISGs could be rescued by exogenous IFN-β supplementation. Activation of the cholesterol-sensing nuclear liver X receptor (LXR) recapitulated the cholesterol-initiated type-I IFN suppression. Additional analyses of murine in vitro and in vivo generated foam cells confirmed the suppressed IFN signalling pathways and suggest that this phenotype is mediated via downregulation of interferon regulatory factor binding at gene promoters. Finally, RNA-seq analysis of monocytes of familial hypercholesterolemia (FH) patients also showed type-I IFN suppression which was restored by lipid-lowering therapy and not present in monocytes of healthy donors. Taken together, we define type-I IFN suppression as an athero-protective characteristic of foamy macrophages. These data provide new insights into the mechanisms that control inflammatory responses in hyperlipidaemic settings and can support future therapeutic approaches focusing on reprogramming of macrophages to reduce atherosclerotic plaque progression and improve stability.
| EGAS00001005955 | EGA
Project description:β-2 Microglobulin (β2M) is a molecular chaperone for the major histocompatibility class I (MHC I) complex, hemochromatosis factor protein (HFE), and the neonatal Fc receptor (FcRn), but β2M may also have less understood chaperone-independent functions. Elevated plasma β2M has a direct role in neurocognitive decline and is a risk factor for adverse cardiovascular events. β2M mRNA is present in platelets at very high levels, and β2M is part of the activated platelet releasate. In addition to their more well-studied thrombotic functions, platelets are important immune regulatory cells that release inflammatory molecules and contribute to leukocyte trafficking, activation, and differentiation. We have now found that platelet-derived β2M is a mediator of monocyte proinflammatory differentiation through noncanonical TGFβ receptor signaling. Circulating monocytes from mice lacking β2M only in platelets (Plt-β2M-/-) had a more proreparative monocyte phenotype, in part dependent on increased platelet-derived TGFβ signaling in the absence of β2M. Using a mouse myocardial infarction (MI) model, Plt-β2M-/- mice had limited post-MI proinflammatory monocyte responses and, instead, demonstrated early proreparative monocyte differentiation, profibrotic myofibroblast responses, and a rapid decline in heart function compared with WT mice. These data demonstrate a potentially novel chaperone-independent, monocyte phenotype-regulatory function for platelet β2M and that platelet-derived 2M and TGFβ have opposing roles in monocyte differentiation that may be important in tissue injury responses.
| S-EPMC6483513 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-02-10 | GSE193152 | GEO
Project description:Macrophages are critical components of atherosclerotic lesions and their pro- and anti-inflammatory responses influence atherogenesis. Type-I interferons (IFNs) are cytokines that play an essential role in antiviral responses and inflammatory activation and have been shown to promote atherosclerosis. Although the impact of type-I IFNs on macrophage foam cell formation is well-documented, the effect of lipid accumulation in monocytes and macrophages on type-I IFN responses remains unknown. Here we examined IFN stimulated (ISG) and non-ISG inflammatory gene expression in mouse and human macrophages that were loaded with acetylated LDL (acLDL), as a model for foam cell formation. We found that acLDL loading in mouse and human macrophages specifically suppressed expression of ISGs and IFN-β secretion, but not other pro-inflammatory genes. The downregulation of ISGs could be rescued by exogenous IFN-β supplementation. Activation of the cholesterol-sensing nuclear liver X receptor (LXR) recapitulated the cholesterol-initiated type-I IFN suppression. Additional analyses of murine in vitro and in vivo generated foam cells confirmed the suppressed IFN signalling pathways and suggest that this phenotype is mediated via downregulation of interferon regulatory factor binding at gene promoters. Finally, RNA-seq analysis of monocytes of familial hypercholesterolemia (FH) patients also showed type-I IFN suppression which was restored by lipid-lowering therapy and not present in monocytes of healthy donors. Taken together, we define type-I IFN suppression as an athero-protective characteristic of foamy macrophages. These data provide new insights into the mechanisms that control inflammatory responses in hyperlipidaemic settings and can support future therapeutic approaches focusing on reprogramming of macrophages to reduce atherosclerotic plaque progression and improve stability.
2022-02-10 | GSE192709 | GEO
Project description:Mononuclear phagocytes (bone marrow monocyte-derived macrophages, alveolar macrophages, perivascular macrophages, and microglia) are reservoirs and vehicles of dissemination for the human immunodeficiency virus type-1 (HIV-1). How virus alters mononuclear phagocyte immunoregulatory activities to complete its life cycle and influence disease is incompletely understood. In attempts to better understanding the influence of virus on macrophage functions, we used one-dimensional electrophoresis, and liquid chromatography tandem mass spectrometry to analyze the secretome of HIV-1-infected human monocyte-derived macrophages. We identified 110 proteins in culture supernatants of control (uninfected) and virus-infected cells. Differentially expressed cytoskeletal, enzymes, redox, and immunoregulatory protein classes were discovered and validated by Western blot tests. These included, but were not limited to, cystatin C, cystatin B, chitinase 3-like 1 protein, cofilin-1, l-plastin, superoxide dismutase, leukotriene A(4) hydrolase, and alpha-enolase. This study, using a unique proteomics platform, provides novel insights into virus-host cell interactions that likely affect the functional role of macrophages in HIV disease.
| S-EPMC1993545 | biostudies-literature