How type I interferons shape myeloid cell function in CNS autoimmunity

S. M. Brendecke; M. Prinz

doi:10.1189/jlb.0112043

Immunotherapy against Metastatic Melanoma with Human iPS Cell–Derived Myeloid Cell Lines Producing Type I Interferons

Cancer Immunology Research ◽

10.1158/2326-6066.cir-15-0096 ◽

2015 ◽

Vol 4 (3) ◽

pp. 248-258 ◽

Cited By ~ 6

Author(s):

Azusa Miyashita ◽

Satoshi Fukushima ◽

Satoshi Nakahara ◽

Yosuke Kubo ◽

Aki Tokuzumi ◽

...

Keyword(s):

Metastatic Melanoma ◽

Cell Lines ◽

Myeloid Cell ◽

Type I Interferons ◽

Type I ◽

Ips Cell

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Inflammation Triggers Liver X Receptor-Dependent Lipogenesis

Molecular and Cellular Biology ◽

10.1128/mcb.00364-19 ◽

2019 ◽

Vol 40 (2) ◽

Author(s):

Sophie R. Liebergall ◽

Jerry Angdisen ◽

Shun Hang Chan ◽

YingJu Chang ◽

Timothy F. Osborne ◽

...

Keyword(s):

Cell Function ◽

Immune Cell ◽

Acid Synthesis ◽

Liver X Receptor ◽

Cholesterol Homeostasis ◽

Type I Interferons ◽

Type I ◽

Liver X Receptors ◽

Inflammatory Signals ◽

X Receptors

ABSTRACT Immune cell function can be modulated by changes in lipid metabolism. Our studies indicate that cholesterol and fatty acid synthesis increases in macrophages between 12 and 18 h after the activation of Toll-like receptors with proinflammatory stimuli and that the upregulation of lipogenesis may contribute to the resolution of inflammation. The inflammation-dependent increase in lipogenesis requires the induction of the liver X receptors, members of the nuclear receptor superfamily of transcription factors, by type I interferons in response to inflammatory signals. Instead of the well-established role for liver X receptors in stimulating cholesterol efflux, we demonstrate that liver X receptors are necessary for the proper resumption of cholesterol synthesis in response to inflammatory signals. Thus, liver X receptors function as bidirectional regulators of cholesterol homeostasis, driving efflux when cholesterol levels are high and facilitating synthesis in response to inflammatory signals. Liver X receptor activity is also required for the proper shutdown of a subset of type I interferon-stimulated genes as inflammation subsides, placing the receptors in a negative-feedback loop that may contribute to the resolution of the inflammatory response.

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Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis

Gut ◽

10.1136/gutjnl-2015-311224 ◽

2016 ◽

Vol 66 (3) ◽

pp. 507-518 ◽

Cited By ~ 27

Author(s):

Carl-Philipp Hackstein ◽

Lisa Mareike Assmus ◽

Meike Welz ◽

Sabine Klein ◽

Timo Schwandt ◽

...

Keyword(s):

Liver Cirrhosis ◽

Liver Fibrosis ◽

Bacterial Infection ◽

Bacterial Infections ◽

Cell Function ◽

Myeloid Cells ◽

Myeloid Cell ◽

Type I ◽

Receptor Signalling ◽

Duct Ligation

ObjectivePatients with liver cirrhosis suffer from increased susceptibility to life-threatening bacterial infections that cause substantial morbidity.MethodsExperimental liver fibrosis in mice induced by bile duct ligation or CCl4application was used to characterise the mechanisms determining failure of innate immunity to control bacterial infections.ResultsIn murine liver fibrosis, translocation of gut microbiota induced tonic type I interferon (IFN) expression in the liver. Such tonic IFN expression conditioned liver myeloid cells to produce high concentrations of IFN upon intracellular infection withListeriathat activate cytosolic pattern recognition receptors. Such IFN-receptor signalling caused myeloid cell interleukin (IL)-10 production that corrupted antibacterial immunity, leading to loss of infection-control and to infection-associated mortality. In patients with liver cirrhosis, we also found a prominent liver IFN signature and myeloid cells showed increased IL-10 production after bacterial infection. Thus, myeloid cells are both source and target of IFN-induced and IL-10-mediated immune dysfunction. Antibody-mediated blockade of IFN-receptor or IL-10-receptor signalling reconstituted antibacterial immunity and prevented infection-associated mortality in mice with liver fibrosis.ConclusionsIn severe liver fibrosis and cirrhosis, failure to control bacterial infection is caused by augmented IFN and IL-10 expression that incapacitates antibacterial immunity of myeloid cells. Targeted interference with the immune regulatory host factors IL-10 and IFN reconstitutes antibacterial immunity and may be used as therapeutic strategy to control bacterial infections in patients with liver cirrhosis.

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Type I interferons directly inhibit regulatory T cells to allow optimal antiviral T cell responses during acute LCMV infection

Journal of Experimental Medicine ◽

10.1084/jem.20131556 ◽

2014 ◽

Vol 211 (5) ◽

pp. 961-974 ◽

Cited By ~ 96

Author(s):

Shivani Srivastava ◽

Meghan A. Koch ◽

Marion Pepper ◽

Daniel J. Campbell

Keyword(s):

T Cells ◽

T Cell ◽

Cell Function ◽

Acute Infection ◽

Cell Activity ◽

T Cell Responses ◽

Type I Interferons ◽

Type I ◽

Cell Responses ◽

Lcmv Infection

Regulatory T (T reg) cells play an essential role in preventing autoimmunity but can also impair clearance of foreign pathogens. Paradoxically, signals known to promote T reg cell function are abundant during infection and could inappropriately enhance T reg cell activity. How T reg cell function is restrained during infection to allow the generation of effective antiviral responses remains largely unclear. We demonstrate that the potent antiviral type I interferons (IFNs) directly inhibit co-stimulation–dependent T reg cell activation and proliferation, both in vitro and in vivo during acute infection with lymphocytic choriomeningitis virus (LCMV). Loss of the type I IFN receptor specifically in T reg cells results in functional impairment of virus-specific CD8+ and CD4+ T cells and inefficient viral clearance. Together, these data demonstrate that inhibition of T reg cells by IFNs is necessary for the generation of optimal antiviral T cell responses during acute LCMV infection.

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Myeloid cell nuclear differentiation antigen controls the pathogen-stimulated type I interferon cascade in human monocytes by transcriptional regulation of IRF7

Nature Communications ◽

10.1038/s41467-021-27701-x ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Lili Gu ◽

David Casserly ◽

Gareth Brady ◽

Susan Carpenter ◽

Adrian P. Bracken ◽

...

Keyword(s):

Rna Polymerase Ii ◽

Gene Promoter ◽

Myeloid Cell ◽

Type I Interferons ◽

Type I ◽

Immune Gene ◽

Type I Ifn ◽

Differentiation Antigen ◽

Nuclear Differentiation ◽

Viral Responses

AbstractType I interferons (IFNs) are critical for anti-viral responses, and also drive autoimmunity when dysregulated. Upon viral sensing, monocytes elicit a sequential cascade of IFNβ and IFNα production involving feedback amplification, but how exactly this cascade is regulated in human cells is incompletely understood. Here we show that the PYHIN protein myeloid cell nuclear differentiation antigen (MNDA) is required for IFNα induction in monocytes. Unlike other PYHINs, this is not due to a pathogen sensing role, but rather MNDA regulated expression of IRF7, a transcription factor essential for IFNα induction. Mechanistically, MNDA is required for recruitment of STAT2 and RNA polymerase II to the IRF7 gene promoter, and in fact MNDA is itself recruited to the IRF7 promoter after type I IFN stimulation. These data implicate MNDA as a critical regulator of the type I IFN cascade in human myeloid cells and reveal a new role for human PYHINs in innate immune gene induction.

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Functional specialization of human circulating CD16 and CD1c myeloid dendritic-cell subsets

Blood ◽

10.1182/blood-2006-08-038422 ◽

2007 ◽

Vol 109 (12) ◽

pp. 5371-5379 ◽

Cited By ~ 145

Author(s):

Diego Piccioli ◽

Simona Tavarini ◽

Erica Borgogni ◽

Veronica Steri ◽

Sandra Nuti ◽

...

Keyword(s):

Cell Function ◽

Umbilical Vein ◽

Type I Interferons ◽

Type I ◽

Colony Stimulating Factor ◽

Tnf Α ◽

Macrophage Colony ◽

Umbilical Vein Endothelial Cells ◽

Factor Α ◽

Stimulating Factor

Abstract Human blood contains 2 populations of dendritic cells (DCs): plasmacytoid and myeloid (mDC). mDCs are subdivided into 3 subsets using the surface markers CD16, CD1c, and BDCA-3. Their role as pathogen sentinels and adjuvant targets was tested by phenotypic and functional analysis. We show that mDC subsets are immature and express mRNA for most toll-like receptors (TLRs), except for TLR3 in CD16-mDCs. The most represented subsets, CD16- and CD1c-mDCs, are similarly responsive to all TLR agonists. Among 31 cytokines tested, both subsets produce CXCL8 (IL-8)/tumor necrosis factor-α (TNF-α)/IL-6/CCL3 (MIP-1α)/CCL4 (MIP-1β)/IL-1β. CXCL8 (IL-8) is the predominant cytokine produced by CD1c-mDCs on TLR engagement, whereas all other cytokines, particularly TNF-α, are secreted in 10-fold to 100-fold higher amounts by CD16-mDCs. CD16-mDCs cocultured with human umbilical vein endothelial cells induce a significantly higher production of CXCL10 (IP-10), granulocyte-macrophage colony-stimulating factor, and granulocyte colony-stimulating factor than CD1c-mDCs. In addition, interleukin-3 and type I interferons are stimuli specifically for DC maturation rather than cytokine secretion, whereas TNF-α is almost ineffective in inducing either function, suggesting a mechanism of T-cell–DC crosstalk and of rapid induction of antigen-presenting cell function during viral infection rather than inflammation. In conclusion, CD16-mDCs show strong proinflammatory activity, whereas CD1c-mDCs appear to be mainly inducers of chemotaxis.

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