Concerted cellular responses to type I interferon propel memory impairment associated with amyloid β plaques

Despite well-documented maladaptive neuroinflammation in Alzheimer's disease (AD), the principal signal that drives memory and cognitive impairment remains elusive. Here, we reveal robust, age-dependent cellular reactions to type I interferon (IFN), an innate immune cytokine aberrantly elicited by beta-amyloid plaques, and examine their role in cognition and neuropathology relevant to AD in a murine amyloidosis model. Long-term blockade of IFN receptor rescued both memory and synaptic deficits and resulted in reduced microgliosis, inflammation, and neuritic pathology. Interestingly, microglia-specific IFN receptor ablation attenuated the loss of post-synaptic terminals, whereas IFN signaling in neural cells contributed to pre-synaptic alteration and plaque accumulation. Intriguingly, IFN pathway activation displayed a strong inverse correlation with cognitive performance, promoting selective synapse engulfment by microglia rather than amyloid plaques. Overall, IFN signaling represents a critical module within the neuroinflammatory network of AD and prompts a concerted cellular state that is detrimental to memory and cognition.

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TMEFF2: A Transmembrane Proteoglycan with Multifaceted Actions in Cancer and Disease

Cancers ◽

10.3390/cancers12123862 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3862

Author(s):

Motasim Masood ◽

Stefan Grimm ◽

Mona El-Bahrawy ◽

Ernesto Yagüe

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Transmembrane Protein ◽

Intracellular Localization ◽

Amyloid Β ◽

Inverse Correlation ◽

Response To Therapy ◽

Endocrine Function ◽

Type I ◽

Amyloid Β Protein

Transmembrane protein with an EGF-like and two Follistatin-like domains 2 (TMEFF2) is a 374-residue long type-I transmembrane proteoglycan which is proteolytically shed from the cell surface. The protein is involved in a range of functions including metabolism, neuroprotection, apoptosis, embryonic development, onco-suppression and endocrine function. TMEFF2 is methylated in numerous cancers, and an inverse correlation with the stage, response to therapy and survival outcome has been observed. Moreover, TMEFF2 methylation increases with breast, colon and gastric cancer progression. TMEFF2 is methylated early during oncogenesis in breast and colorectal cancer, and the detection of methylated free-circulating TMEFF2 DNA has been suggested as a potential diagnostic tool. The TMEFF2 downregulation signature equals and sometimes outperforms the Gleason and pathological scores in prostate cancer. TMEFF2 is downregulated in glioma and cotricotropinomas, and it impairs the production of adrenocorticotropic hormone in glioma cells. Interestingly, through binding the amyloid β protein, its precursor and derivatives, TMEFF2 provides neuroprotection in Alzheimer’s disease. Despite undergoing extensive investigation over the last two decades, the primary literature regarding TMEFF2 is incoherent and offers conflicting information, in particular, the oncogenic vs. onco-suppressive role of TMEFF2 in prostate cancer. For the first time, we have compiled, contextualised and critically analysed the vast body of TMEFF2-related literature and answered the apparent discrepancies regarding its function, tissue expression, intracellular localization and oncogenic vs. onco-suppressive role.

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Type I Interferons in Autoimmune Disease

Annual Review of Pathology Mechanisms of Disease ◽

10.1146/annurev-pathol-020117-043952 ◽

2019 ◽

Vol 14 (1) ◽

pp. 369-393 ◽

Cited By ~ 46

Author(s):

Mary K. Crow ◽

Mikhail Olferiev ◽

Kyriakos A. Kirou

Keyword(s):

Systemic Lupus Erythematosus ◽

Immune System ◽

Lupus Erythematosus ◽

Type I Interferon ◽

Type I Interferons ◽

Type I ◽

Systemic Lupus ◽

Pathway Activation ◽

Interferon Pathway ◽

Chronic Activation

Type I interferons, which make up the first cytokine family to be described and are the essential mediators of antivirus host defense, have emerged as central elements in the immunopathology of systemic autoimmune diseases, with systemic lupus erythematosus as the prototype. Lessons from investigation of interferon regulation following virus infection can be applied to lupus, with the conclusion that sustained production of type I interferon shifts nearly all components of the immune system toward pathologic functions that result in tissue damage and disease. We review recent data, mainly from studies of patients with systemic lupus erythematosus, that provide new insights into the mechanisms of induction and the immunologic consequences of chronic activation of the type I interferon pathway. Current concepts implicate endogenous nucleic acids, driving both cytosolic sensors and endosomal Toll-like receptors, in interferon pathway activation and suggest targets for development of novel therapeutics that may restore the immune system to health.

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The Type I Interferon Response Determines Differences in Choroid Plexus Susceptibility between Newborns and Adults in Herpes Simplex Virus Encephalitis

mBio ◽

10.1128/mbio.00437-16 ◽

2016 ◽

Vol 7 (2) ◽

Cited By ~ 19

Author(s):

Douglas R. Wilcox ◽

Stephen S. Folmsbee ◽

William J. Muller ◽

Richard Longnecker

Keyword(s):

Choroid Plexus ◽

Type I Interferon ◽

Adult Brain ◽

Interferon Response ◽

Type I ◽

Β Receptor ◽

Simplex Virus ◽

The Brain ◽

Hsv 1

ABSTRACTNewborns are significantly more susceptible to severe viral encephalitis than adults, with differences in the host response to infection implicated as a major factor. However, the specific host signaling pathways responsible for differences in susceptibility and neurologic morbidity have remained unknown. In a murine model of HSV encephalitis, we demonstrated that the choroid plexus (CP) is susceptible to herpes simplex virus 1 (HSV-1) early in infection of the newborn but not the adult brain. We confirmed susceptibility of the CP to HSV infection in a human case of newborn HSV encephalitis. We investigated components of the type I interferon (IFN) response in the murine brain that might account for differences in cell susceptibility and found that newborns have a dampened interferon response and significantly lower basal levels of the alpha/beta interferon (IFN-α/β) receptor (IFNAR) than do adults. To test the contribution of IFNAR to restricting infection from the CP, we infected IFNAR knockout (KO) adult mice, which showed restored CP susceptibility to HSV-1 infection in the adult. Furthermore, reduced IFNAR levels did not account for differences we found in the basal levels of several other innate signaling proteins in the wild-type newborn and the adult, including protein kinase R (PKR), that suggested specific regulation of innate immunity in the developing brain. Viral targeting of the CP, a region of the brain that plays a critical role in neurodevelopment, provides a link between newborn susceptibility to HSV and long-term neurologic morbidity among survivors of newborn HSV encephalitis.IMPORTANCECompared to adults, newborns are significantly more susceptible to severe disease following HSV infection. Over half of newborn HSV infections result in disseminated disease or encephalitis, with long-term neurologic morbidity in 2/3 of encephalitis survivors. We investigated differences in host cell susceptibility between newborns and adults that contribute to severe central nervous system disease in the newborn. We found that, unlike the adult brain, the newborn choroid plexus (CP) was susceptible early in HSV-1 infection. We demonstrated that IFN-α/β receptor levels are lower in the newborn brain than in the adult brain and that deletion of this receptor restores susceptibility of the CP in the adult brain. The CP serves as a barrier between the blood and the cerebrospinal fluid and plays a role in proper neurodevelopment. Susceptibility of the newborn choroid plexus to HSV-1 has important implications in viral spread to the brain and, also, in the neurologic morbidity following HSV encephalitis.

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Autoantibody Specificities and Type I Interferon Pathway Activation in Idiopathic Inflammatory Myopathies

Scandinavian Journal of Immunology ◽

10.1111/sji.12449 ◽

2016 ◽

Vol 84 (2) ◽

pp. 100-109 ◽

Cited By ~ 13

Author(s):

L. Ekholm ◽

S. Vosslamber ◽

A. Tjärnlund ◽

T. D. de Jong ◽

Z. Betteridge ◽

...

Keyword(s):

Type I Interferon ◽

Idiopathic Inflammatory Myopathies ◽

Type I ◽

Inflammatory Myopathies ◽

Pathway Activation ◽

Interferon Pathway

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The Type I Interferon Response and Age-Dependent Susceptibility to Herpes Simplex Virus Infection

DNA and Cell Biology ◽

10.1089/dna.2017.3668 ◽

2017 ◽

Vol 36 (5) ◽

pp. 329-334 ◽

Cited By ~ 4

Author(s):

Daniel Giraldo ◽

Douglas R. Wilcox ◽

Richard Longnecker

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Infection ◽

Herpes Simplex Virus Infection ◽

Type I Interferon ◽

Interferon Response ◽

Type I ◽

Age Dependent ◽

Simplex Virus

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Next generation of tumor-activating type I IFN enhances anti-tumor immune responses to overcome therapy resistance

Nature Communications ◽

10.1038/s41467-021-26112-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Xuezhi Cao ◽

Yong Liang ◽

Zhenxiang Hu ◽

Huiyu Li ◽

Jiaming Yang ◽

...

Keyword(s):

Tumor Microenvironment ◽

Immune Responses ◽

Half Life ◽

Tumor Targeting ◽

Type I Interferon ◽

Therapy Resistance ◽

Type I ◽

Type I Ifn ◽

Targeting Effect

AbstractType I interferon is promising in treating different kinds of tumors, but has been limited by its toxicity, lack of tumor targeting, and very short half-life. To target tumors, reduce systemic toxicity, and increase half-life, here we engineer a masked type I IFN-Fc (ProIFN) with its natural receptor connected by a cleavable linker that can be targeted by tumor-associated proteases. ProIFN has a prolonged serum half-life and shows an improved tumor-targeting effect. Interestingly, ProIFN-treated mice show enhanced DC cross-priming and significant increased CD8+ infiltration and effector function in the tumor microenvironment. ProIFN is able to improve checkpoint blockade efficacy in established tumors, as well as radiation efficacy for both primary and metastatic tumors. ProIFN exhibits superior long-term pharmacokinetics with minimal toxicity in monkeys. Therefore, this study demonstrates an effective tumor-activating IFN that can increase targeted immunity against primary tumor or metastasis and reduce periphery toxicity to the host.

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Effects of Long-Term Type I Interferon on the Arterial Wall and Smooth Muscle Progenitor Cells Differentiation

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.115.306767 ◽

2016 ◽

Vol 36 (2) ◽

pp. 266-273 ◽

Cited By ~ 15

Author(s):

Yanpeng Diao ◽

Rajesh Mohandas ◽

Pui Lee ◽

Zhiyu Liu ◽

Larysa Sautina ◽

...

Keyword(s):

Smooth Muscle ◽

Progenitor Cells ◽

Arterial Wall ◽

Type I Interferon ◽

Type I ◽

Muscle Progenitor Cells ◽

Term Type

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Role of type I interferon signaling and microglia in the abnormal long term potentiation and object place recognition deficits of male mice with a mutation of the Tuberous Sclerosis 2 gene

10.1101/2021.09.27.461827 ◽

2021 ◽

Author(s):

Manuel F López-Aranda ◽

Gayle M Boxx ◽

Miranda Phan ◽

Karen Bach ◽

Rochelle Mandanas ◽

...

Keyword(s):

Type I Interferon ◽

Long Term Potentiation ◽

Null Mutation ◽

Type I ◽

Place Recognition ◽

Interferon Signaling ◽

Male Mice ◽

Term Potentiation

Tuberous Sclerosis Complex (TSC) is a genetic disorder associated with high rates of intellectual disability and autism. Although previous studies focused on the role of neuronal deficits in the memory phenotypes of rodent models of TSC, the results presented here demonstrate a role for microglia in these deficits. Mice with a heterozygous null mutation of the Tsc2 gene (Tsc2+/-), show deficits in hippocampal dependent tasks, as well as abnormal long-term potentiation (LTP) in the hippocampal CA1 region. Here, we show that microglia and type I interferon signaling (IFN1) have a key role in the object place recognition (OPR; a hippocampal dependent task) deficits and abnormal LTP of Tsc2+/- male mice. Unexpectedly, we demonstrate that male, but not female, Tsc2+/- mice showed OPR deficits. Importantly, these deficits can be rescued by depletion of microglia, as well as by a genetic manipulation of a signaling pathway known to modulate microglia function (interferon-alpha/beta receptor alpha chain null mutation). In addition to rescuing the OPR deficits, depletion of microglia also reversed the abnormal LTP of the Tsc2+/- mice. Altogether, our results suggest that altered IFN1 signaling in microglia cause the abnormal LTP and OPR deficits of male Tsc2+/- mice.

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