Table 1. Summary of the production and the effect of type-I IFNs in atherosclerosis-associated cells.
| Cell/tissue | Type-I IFN production/induction | Responses to type-I IFNs | Human sample | Murine model | Reference |
|---|---|---|---|---|---|
| Aortic tissue | Increased SiglecH and Ifna expression in the aortic tissue and elevated IFN-α in the serum in mice with HFD | Apoe−/− (in vivo) aorta, HFD vs. ND for 12 wk | Döring et al., 2012 | ||
| B cell | Increased type-I IFN expression/secretion in B cell stimulated by Mtb (in vivo and in vitro) | Reduced type-I IFN production in Ifnar1−/− B cells | Ifnar1−/−, Sting−/−, WT pulmonary tissue, pleural fluid, and spleen | Bénard et al., 2018 | |
| B cell | Ifnar1−/− mice showed reduced auto-Ab production | Ifnar1−/−, WT BM chimera | Domeier et al., 2018 | ||
| B cell | Increased anti-dsDNA Ab serum levels in symptomatic vs. asymptomatic carotid artery stenosis patients | Carotid artery stenosis patients | Döring et al., 2012 | ||
| B cell | Elevated anti-dsDNA Ab in IFN-α/CpG-treated/HFD-fed mice and dampened by pDC depletion by PDCA1 Ab in Apoe−/− mice or in Cramp−/− mice (Ldlr−/−) | Apoe−/− (in vivo), HFD vs. ND, Ldlr−/− Cramp+/+ vs. Cramp−/−, ± IFN-α/CpG treatment | Döring et al., 2012 | ||
| B cell | Reduced anti-dsDNA Ab in tofacitinib treated mice | MRL/lpr mice ± tofacitinib | Furumoto et al., 2017 | ||
| B cell | Ifnb1−/− B cells showed suboptimal responses toward TLR7 stimulation | Reduced cytokine production in Ifnar1−/− B cell upon TLR stimulation, exogenous type-I IFNs strengthen the responses | Ifnar1−/−, Ifnb1−/−, WT spleen | Green et al., 2009 | |
| B cell | Transitional B cell subsets express type-I IFNs | Endogenous IFN-β promotes survival and development of transitional (autoreactive) B cells | Ifnb1−/−, Rag1−/−, WT | Hamilton et al., 2017 | |
| B cell | Autoantibodies against neutrophil antimicrobial peptides is associated with seurm IFN-α in SLE patients | SLE patients | Lande et al., 2011 | ||
| B cell | Reduced Ab production as a response to poly(I:C) in Ifnar1−/− B cells | Ifnar1−/−, WT | Swanson et al., 2010 | ||
| B cell | B cells from SLE patients produce IFN-α | SLE PBMC | Ward et al., 2016 | ||
| EC | SLE serum induced more ISGs compared with HC, IFN-α suppressed NO production and increases CCL2 and VCAM-1 expression and neutrophil migration | HUVEC, SLE patients vs. HC sera | Buie et al., 2017 | ||
| EC | Interrupted CD31 staining (EC damage) in vasculature of mice expressing IFN-α | In vivo Ifna5 expressing model (plasmid transduced, 3 wk) vs. WT | Diao et al., 2016 | ||
| EC | IFN-β1a induces membrane-bound ICAM protein expression | HUVEC | Giorelli et al., 2002 | ||
| EC | IFN-β but not IFN-α inhibits HUVEC proliferation and survival, both type-I IFNs reduce HUVEC NO production | HUVEC | Jia et al., 2018 | ||
| EC | ICAM-1, VCAM-1 adnd osinophil adhesion was significantly augmented by IFN-β in the presence of TNF-α but not in its absence | HUVEC | Kobayashi et al., 2008 | ||
| EC | Type-I IFNs induce CCL5, CX3CL1 production via JAK signaling | HUVEC, HPAEC, HAEC, HLMVEC | Nakano et al., 2012 | ||
| EC | IFNα2b does not affect HAEC proliferation and NO production | HAEC | Reynolds et al., 2014 | ||
| EC | Type-I IFNs inhibit the growth factor deprivation- or oxidative cytotoxicity-induced cell death | HAEC | Sano et al., 2012 | ||
| EC | Type-I IFNs alone did not affect the expression of E-selectin, P-selectin, VCAM-1, and ICAM-1 | HUVEC | Shen et al., 1997 | ||
| EC | TNFR1, TNFR2 signaling induce IRF1 expression and IFN-β production in MHEC | IFN-β increased VCAM-1, CXCR3 chemokines (Cxcl9, Cxcl10) expression in MHEC supporting monocyte recruitment | Ifnar1−/−, WT MHEC with/without IFN-β treatment | Venkatesh et al., 2013 | |
| EC/EPC | SLE serum/IFN-α prevents monolayer formation and maturation from EPC and induces apoptosis, SLE EPC restores a normal phenotype with IFNA(R) blockade | SLE patient serum, EPC | Denny et al., 2007 | ||
| EC/EPC | Improved endothelium-dependent vasorelaxation, EPC differentiation in tofacitinib treated mice | MRL/lpr mice ± tofacitinib, aorta | Furumoto et al., 2017 | ||
| EC/EPC | IFN-α suppresses EPC differentiation | Murine bone marrow and spleen EPC | Thacker et al., 2010 | ||
| EC/EPC | Loss of type-I IFN signaling improves EPC number and EC function in lupus-prone mice while additional IFN-α worsens EC function and EPC differentiation | IFNαβR−/− or IFNαβR+/+ and lupus-prone vs. normal mice, ± Ifna-expressing virus, Apoe−/− IFNαβR−/− mice WD for 10 wk | Thacker et al., 2012 | ||
| Eosinophil | oxLDL up-regulates IFN-α and IFN-β (CD36 dependent), reduce IL-4/IL13 expression | BM-derived eosinophils (in vitro), ± anti-CD36 Mab, ± Cd36 siRNA | Qin et al., 2017 | ||
| EPC | Increased IFN signature of PBMC and reduced differentiation capacity of EPC in APS patients or EPC treated with APS sera, which could be rescued by anti-IFNAR Ab | APS/SLE patients vs. HC PBMC | Grenn et al., 2017 | ||
| mDC | Pro-IL-1β synthesis and IL-1β maturation are unaffected by type-I IFNs | WT BMDC ± type-I IFNs | Guarda et al., 2011 | ||
| mDC | IFN-α increases TNF expression upon LPS stimulation | MoDC (in vitro) | Niessner et al., 2007 | ||
| mDC | Combining IFN-α with LPS amplifies TNF expression while IFN-α alone does not affect TNF expression (JAK/STAT, NF-κB dependent) but increases TLR4 expression | MoDC (in vitro) | Niessner et al., 2007 | ||
| Monocyte | Tofacitinib and JAK1 inhibitor increase IL6 and reduce CXCL10, TNF production in monocyte stimulated with LPS+IFNγ | HC monocyte ± tofacitinib/JAK1 inhibitor/JAK3 inhibitor | De Vries et al., 2019 | ||
| Monocyte | Reduced recruitment to peritoneal cavity in WT mice upon poly(I:C) followed by TLR4 intraperitoneal injection, but the reduction is reduced in Ifnar1−/− mice | Ifnar1−/−, WT mice ± poly(I:C) followed by alum intraperitoneal injection | Guarda et al., 2011 | ||
| Monocyte | In vitro IFN-β priming or IFN-β treatment in MS patients suppresses IL-1β production in monocyte upon LPS/Alum stimulation | treated MS vs. HC monocyte ± IFN-β, LPS, Alum | Guarda et al., 2011 | ||
| Monocyte | Increased oxLDL uptake in SLE patient monocyte | SLE patients vs. HC | Li et al., 2011a | ||
| Monocyte | IFN-α increases TNF expression upon LPS stimulation | THP1 (in vitro) | Niessner et al., 2007 | ||
| Monocyte | Increased lipid content and LDL uptake via upregulation of SR-A in HIV patients or HC with IFN-α treatment (correlates with MX1, CXCL10 expression) | HIV patients vs. HC, ± IFN-α | Pulliam et al., 2014 | ||
| Monocyte | Ifna1high Ly-6C− monocyte subsets identified | Apoe−/− (in vivo) plaque | Fig. 3 in Winkels et al., 2018 | ||
| Monocyte/Mφ | Increased CCL5-dependent leukocyte arrest in the carotid arteries upon IFN-β treatment | Apoe−/− (in vivo) plaque, ± IFN-β 1 d, ± Met-Rantes, HFD 3 wk | Goossens et al., 2010 | ||
| Mφ | IFN-α treatment altered gene expression enriched in metabolism pathways, such as lipid metabolism | MDM (in vitro) ± IFN-α | BMM (in vitro) | Ahmed et al., 2018 | |
| Mφ | Mtb-treated B cell–conditioned media induce expression of Cox2, Nos2, PDL-1 in WT BMMs which is abrogated in Ifnar−/− BMMs | Ifnar1−/−, WT BMM | Bénard et al., 2018 | ||
| Mφ | Increased foam cell formation via upregulation of SR-A with IFN-β treatment | BMM (in vitro), PM (Ldlr−/−, HFD 10 wk, in vivo) | Boshuizen et al., 2016 | ||
| Mφ | TNF is restricted by IFN-γ priming but potentiated by IFN-β priming, the effect of timing is gene- and stimulus-specific | Cheng et al., 2019 | |||
| Mφ | Tofacitinib and JAK1 inhibitor reduce IL6, CXCL10, TNF production and pro-inflammatory gene expression in BMM stimulated with LPS+IFNγ | WT BMM ± tofacitinib/JAK1 inhibitor/JAK3 inhibitor | De Vries et al., 2019 | ||
| Mφ | Increased IFNAR1/STAT1-dependent CCR2, CCR5, CCL5 expression, EC adhesion upon IFN-α/β treatment | BMM (in vitro, WT, Ifnar1−/−, Stat1−/−) | Goossens et al., 2010 | ||
| Mφ | Increased CCR5, CCL5 expression/secretion upon IFN-α/β treatment | MDM (in vitro) | Goossens et al., 2010 | ||
| Mφ | IFN-β suppresses pro-IL-1β synthesis and IL-1β maturation via IL10 and STAT3 signaling, and suppresses NLRP3 inflammasome activation via STAT1 | Ifnar1−/−, Stat3−/−, Stat1−/−, Il10−/−, Asc−/−, Nlrp3−/− WT BMM, ± type-I IFNs | Guarda et al., 2011 | ||
| Mφ | oxLDL loading suppresses Ifnb1 expression | PM | Jongstra-Bilen et al., 2017 | ||
| Mφ | Macrophage cluster with upregulated ISGs is identified | Ldlr−/− (in vivo) plaque | Kim et al., 2018 | ||
| Mφ | Increased oxLDL uptake, foam cell formation via upregulation of SR-A with IFN-α treatment (could be blocked by anti-IFN-α Ab, B18R or anti-SRA Ab) | THP1-derived macrophage, MDM, ± IFN-α, ± B18R | Li et al., 2011a | ||
| Mφ | IFN signaturehigh macrophage subset enriched in progressing plaque | Ldlr−/− (in vivo) plaque | Lin et al., 2019 | ||
| Mφ | IFN-α abrogates TNF-mediated tolerance, increases Ifnb1 expression. Similar ATAC-seq profile resembling IFN-α in vitro could be found in SLE monocytes | MDM (in vitro), SLE monocytes | Park et al., 2017 | ||
| Mφ | Tofacitinib restore IFN-γ-inhibited ABCA1 protein expression and IFN-γ–increased lipid accumulation | THP-1 ± tofacitinib ± IFN-γ ± HFD rabbit serum or oxLDL | Pérez-Baos et al., 2017 | ||
| Mφ | oxLDL down-regulates IFN-α and IFN-β | PM (in vitro) | Qin et al., 2017 | ||
| Mφ | IFN stimulated gene Ch25h−/− macrophages produce more IL-1β | Ch25h−/−, WT BMM | Reboldi et al., 2014 | ||
| Mφ | HFD suppresses Irf1, Ifnb1 in Ldlr−/− PM | PM (Ldlr−/−, HFD vs. NHD 12 wk) | Table S1 B in Spann et al., 2012 | ||
| Mφ | Tofacitinib treatment supresses pro-inflammatory gene expression and increases ABCA1 and anti-inflammatory gene expression reducing foam cell formation | WT ± tofacitinib, PM, + oxLDL | Wang et al., 2017 | ||
| Mφ | Tofacitinib treatment reduces pro-inflammatory and increase anti-inflammatory PM cell number, gene expression (in vivo) | Apoe−/− mice ± tofacitinib, atherogenic diet, PM | Wang et al., 2017 | ||
| Neutrophil | Increased type-I IFN production in LDGs | SLE patients | Denny et al., 2010 | ||
| Neutrophil | Decreased NET formation in tofacitinib treated bone marrow–derived neutrophils | MRL/lpr mice ± tofacitinib | Furumoto et al., 2017 | ||
| Neutrophil | Increased NET formation in SLE neutrophils could promote type-I IFN induction from pDCs | Increased IFN signaling pathway in neutrophil from SLE patients or treated with SLE serum | SLE patients vs. HC | Garcia-Romo et al., 2011 | |
| Neutrophil | IFN-α treatment/SLE serum induce TLR7 expression | HC ± IFN-α | Garcia-Romo et al., 2011 | ||
| Neutrophil | Reduced recruitment to peritoneal cavity in WT mice upon poly(I:C) followed by TLR4 intraperitoneal injection, but the reduction is ablogated in Ifnar1−/− mice | Ifnar1−/−, WT mice ± poly(I:C) followed by alum intraperitoneal injection | Guarda et al., 2011 | ||
| Neutrophil | Increased NET formation in SLE neutrophils/SLE serum, immune complexes, or monomeric Ig could promote type-I IFN production from pDCs | SLE patients vs. HC | Lande et al., 2011 | ||
| Neutrophil | Increased NET formation, mtROS in LDGs could promote type-I IFN induction in vivo | SLE/CGD patients | WT, Tmem173−/−, Myd88−/− (in vivo induction of type-I IFNs) | Lood et al., 2016 | |
| Neutrophil | Increased NETosis in SLE neutrophils which could promote IFN-α induction from pDCs, and induce apoptosis in ECs partially via NET | SLE patients vs. HC neutrophil/LDG ± Mnase, Gen2.2, HUVEC | Villanueva et al., 2011 | ||
| PBMC | upregulated SRA expression in their PBMC (positively correlates with ISGs: MX1, OAS1) | SLE patients vs. HC | Li et al., 2011a | ||
| PBMC/monocyte | NET-derived 8-OHdG+ DNA is a potent inducer of IFNB1 in PBMC and THP-1 | PBMC, THP1 | Lood et al., 2016 | ||
| pDC | Exacerbated atherosclerosis with unaltered IFN-α serum levels in pDC-depleted mice (by 120G8 mAb administration) | Ldlr−/− (in vivo) plaque, ± 120G8, HFD + carotid artery bilateral placement of semiconstrictive collars | Daissormont et al., 2011 | ||
| pDC | Increased pDC mRNA sigatures/LL37 and BDCA2 staining in the advanced plaques | Early vs. advanced carotid artery specimens | Döring et al., 2012 | ||
| pDC | Decreased plaque sizes, anti-dsDNA Ab titers, and IFN-α serum levels in pDC-depleted mice (by anti-PDCA1 Ab injection) | Apoe−/− (in vivo) plaque, ± anti-PDCA1, HFD | Döring et al., 2012 | ||
| pDC | Cramp/DNA complexes and high-anti-dsDNA Ab-titer serum induce pDC-dependent IFN-α production | Apoe−/− (in vivo) Cramp/DNA complexes injection three times/wk for 4 wk, ± anti-PDCA1 | Döring et al., 2012 | ||
| pDC | Increased IFN-α production upon treatment with serum containing high anti-dsDNA Ab titers | isolated pDC (in vitro) | Döring et al., 2012 | ||
| pDC | Anti-dsDNA IgE trigger pDC IFN-α production | HC PBMC, SLE sera | Henault et al., 2016 | ||
| pDC | Decreased plaque sizes (reduced macrophage area, increased collagen) in pDC-depleted mice, but serum and plaque IFN-α was undetectable | Apoe−/− (in vivo) plaque, ± anti-PDCA1, HFD | Macritchie et al., 2012 | ||
| pDC | Expressing IFN-α in the plaque | Plaque (IHC staining) | Niessner et al., 2006 | ||
| pDC | pDC from hydroxychloroguine-treated SLE patients showed decreased IFN-α production upon TLR7/9 stimulation | SLE vs. HC pDC ± TLR7/9 ligands | Sacre et al., 2012 | ||
| pDC | Upon TLR9 in vivo/in vitro challenge, isolated, in vivo expended aortic pDC secret IFN-α, native aortic pDC expressed PDC-TREM and Ifnb1 | WT aorta, Ldlr−/−, Humanized mice (in vivo) plaque, WD for 10 wk | Yun et al., 2016 | ||
| Plaque | Upregulated IFN signaling pathways in ruptured plaques | Ruptured vs. stable carotid endarterectomy specimens | Goossens et al., 2010 | ||
| Plaque | Increased plaque size in IFN-α treated mice | Ldlr−/−, HFD ± IFN-α treatment for 5 wk | Levy et al., 2003 | ||
| Plaque | Increased IFNA expression is associated with instability without treatment, TLR9 ligands trigger IFN-α production in the plaque | Plaque | Niessner et al., 2006 | ||
| Plaque | TLR9 ligands trigger IFN-α secretion | IFN-α increases LPS-triggered TNF secretion | Plaque | Niessner et al., 2007 | |
| Plaque | CpG treatment increases IFN-α+ cells and secreted IFN-α | Combining IFN-α with LPS amplifies TNF, IL12, IL23, MMP9 expression while IFN-α alone does not affect the expression | Plaque (IHC staining) | Niessner et al., 2007 | |
| Plaque | No changes in plaque sizes, neutrophil, T cell counts, collagen, necrosis | Ldlr−/− or Apoe−/− ± anti-IFNAR1 Ab for 4 wk, HFD for 10 wk | Teunissen et al., 2015 | ||
| Plaque (DCs) | pDC and mDC are present in the shoulder region of human atherosclerotic plaques | Human plaque | Niessner et al., 2007 | ||
| Plaque (Mφ) | Increased macrophage area in plaque with IFN-α injection | Apoe−/− (in vivo) plaque, ± IFN-α two times per wk for 4 wk, HFD | Döring et al., 2012 | ||
| Plaque (Mφ) | Increased macrophage area in plaque with IFN-β injection | Ldlr−/− (in vivo) plaque, ± IFN-β for 3 wk, HFD for 6 wk | Goossens et al., 2010 | ||
| Plaque (Mφ) | Reduced macrophage area in plaque from Ifnar−/− BMT | Myeloid Ifnar−/− vs. WT BMT to Ldlr−/−, HFD 11 wk | Goossens et al., 2010 | ||
| Plaque (Mφ) | Increased macrophage area, decreased apoptosis, no differences in pro-/anti-inflammatory macrophage gene expression | Ldlr−/− ± anti-IFNAR1 Ab for 4 wk, HFD for 10 wk | Teunissen et al., 2015 | ||
| Plaque (Mφ) | Tofacitinib treatment reduces plaque macrophage and lipid area | Apoe−/− mice ± tofacitinib, atherogenic diet | Wang et al., 2017 | ||
| Plaque (necrosis) | Reduced necrotic area in plaque from Ifnar−/− BMT, no differences in IFN-β treated mice, compared with WT untreated controls | Ldlr−/− (in vivo) plaque, ± IFN-β for 3 wk, myeloid Ifnar−/− vs. WT BMT to Ldlr−/− | Goossens et al., 2010 | ||
| Plaque (neutrophil) | NET detected in the vicinity of EGFP+ neutrophils in the plaque in the monocyte depleted mice as early as 2 wk after HFD | Clodronate-containing liposome injection-induced monocyte-depleted LysmEGFP/EGFPApoe−/−, HFD | Döring et al., 2012 | ||
| Plaque (neutrophil) | Increased Cramp mRNA and CRAMP protein in the vicinity of the segment-nucleated neutrophils in the plaques | Apoe−/− (in vivo) aorta, HFD vs. ND for 12 wk | Döring et al., 2012 | ||
| Plaque (neutrophil) | Reduced neutrophil area in plaque from Ifnar−/− BMT, but no changes in IFN-β treated mice | Myeloid Ifnar−/− vs. WT BMT to Ldlr−/−, ± IFN-β, HFD for 11 wk | Goossens et al., 2010 | ||
| Plaque (neutrophil) | Increased Ifna expression, NET formation in arteries from HFD old mice, which could be inhibited by Cl−amidine | Atheroprotective Cl−amidine treatment is NET-IFNAR dependent | Apoe−/− (in vivo) plaque, ± Cl−amidine for 11 wk | Knight et al., 2014 | |
| Plaque (pDC) | Unchanged Ifna expression after pDC-selective deprivation | Ldlr−/− (in vivo) plaque, WD for 7 wk | Yun et al., 2016 | ||
| Platelet | Increased protein expression of CD58, CD69, IFITM1 and PRKRA, increased activation markers (Annexin V binding and platelet–monocyte complexes) | SLE patients (platelet) | Lood et al., 2010 | ||
| Platelet | Reduced time of cloting, increase secreted P-selectin in mice | IFNαβR−/− or IFNαβR+/+ and lupus-prone vs. normal mice, ± Ifna-expressing virus, Apoe−/− IFNαβR−/− mice WD for 10 wk | Thacker et al., 2012 | ||
| SMC/SMPC | IFN-α affects maturation of SMPC (in vivo and in vitro), increases pre-atherosclerotic-like lesions but no significant changes on medial SMC density or thickness (in vivo) | In vivo Ifna5 expressing model (plasmid transduced, 3 wk) vs. WT, IFN-I (in vitro), WT vs. Ifnar−/−, PBMC | Diao et al., 2016 | ||
| T cell | Loss of IFNAR signaling promotes T reg function and proliferation | T reg–specific (Foxp3) IFNAR deficient | Gangaplara et al., 2018 | ||
| T cell | IFN-α suppresses T reg activation, SLE-plasma exert comparable results which could be rescued by IFN-α/β receptor blocking Ab | PBMC, SLE plasma | Golding et al., 2010 | ||
| T cell | IFN-α and IFN-β, but not IFN-γ induce TRAIL expression on CD4+/CD8+ T cells, improving cytotoxicity against tumor cell lines | HC peripheral blood T | Kayagaki et al., 1999 | ||
| T cell | Reduced number of Ifnar−/− T subsets in mixed BM chimeras models, T regs lack of IFNAR show an impairment of immunomodulating function and survival | T reg–specific (Foxp3)/full IFNAR deficient | Metidji et al., 2015 | ||
| T cell | TRAIL colocalizes with IFN-α in the plaque, IFN-α–primed plaque-isolated/blood-derived T cells enhances SMC apoptosis | Plaque (IHC staining, T cell isolation), PBMC | Niessner et al., 2006 | ||
| T cell | Type-I IFNs suppress T reg activation and proliferation and promote other effector T cells' function | Trex1−/−, Trex1−/−Rag2−/−, Trex1−/−Ifnar1−/− (in vivo, colitis) | Srivastava et al., 2014a | ||
| T cell | IFN-β-IFNAR signaling inhibits T reg proliferation | Ifnar1−/− vs. WT | Srivastava et al., 2014b |
Ab, antibody; BMDC, bone marrow–derived dendritic cell; BMM, bone marrow–derived macrophage; BMT, bone marrow transplantation; CGD, chronic granulomatous disease; DC, dendritic cell; HFD, high-fat diet; HLMVEC, human lung microvascular EC; HPAEC, human pulmonary artery EC; Mφ, macrophage; MoDC, monocyte-derived dendritic cell; Mtb, Mycobacterium tuberculosis; mtROS, mitochondrial ROS; ND, normal diet; PM, peritoneal macrophage; SMPC, smooth muscle progenitor cell; WD, Western diet.