The Role of Interferons in Inflammation and Inflammasome Activation

Kopitar-Jerala, Nataša

doi:10.3389/fimmu.2017.00873

Cited by 203 publications

(173 citation statements)

References 123 publications

Supporting

Mentioning

147

Contrasting

Unclassified

Order By: Relevance

“…An autoimmune etiology, however, seems not compatible to the unilateral affection in RE. TLR3 and TLR7 downstream signaling furthermore can lead to inflammasome gene activation [26, 34] shown already in stage 0 PNs. Furthermore, TLR3 and TLR7 can induce the high levels of interferon α / β , pro-inflammatory cytokines and chemokines [7, 11, 24], as shown in stage 1 and 2.…”

Section: Discussionmentioning

confidence: 99%

Microglial nodules provide the environment for pathogenic T cells in human encephalitis

et al. 2019

View full text Add to dashboard Cite

Microglia nodule formation is a common feature in inflammatory brain diseases mediated by T lymphocytes such as viral and paraneoplastic encephalitis, multiple sclerosis, and Rasmussen encephalitis (RE). However, its role has not been fully understood yet. We hypothesized that, in RE, microglial nodules provide an environment for the initiation of the later dominating T-cell cytotoxicity. In RE stage 0, small primary microglia nodules could be identified in the absence of T cells. These primary nodules showed inflammasome activation and endosomal Toll-like receptor upregulation. In stage 1, T cells migrate into the parenchyma and intermingle with microglial cells, thereby forming secondary nodules in which neurons are destroyed. Whole-genome transcriptome analysis at this point showed upregulation of several inflammatory pathways including interferon signaling and major histocompatibility complex-I signaling. Inflammatory profiles, like the ones observed in RE, could be induced upon TLR3 stimulation in neonatal microglial cell cultures. Taken together, our results point towards activation of endosomal TLRs, resulting in increased interferon signaling, inflammasome activation, and chemokine upregulation as early steps in RE pathogenesis. This activity sets the scene for subsequent infiltration of T cells and destruction of neurons. Similar to RE, this microglial microenvironment might be a crucial step in other T-cell-mediated inflammatory brain diseases.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-01958-5) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Microglial nodules provide the environment for pathogenic T cells in human encephalitis

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Infection by bacteria, viruses, fungi, parasites, and other pathogens elicit local and systemic inflammatory responses [37,38], of which sepsis is a leading cause of mortality in adults and children [39,40]. Since inflammation and innate immunity against bacteria are hallmarks of sepsis [41,42], enhancing the latter while mitigating the former is a worthwhile therapeutic strategy [43].…”

Section: Discussionmentioning

confidence: 99%

Klf4 Alleviates Lipopolysaccharide-Induced Inflammation by Inducing Expression of MCP-1 Induced Protein 1 to Deubiquitinate TRAF6

Jia

Han

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Inflammation is an essential component of innate immunity against pathogens, but is tightly regulated, such as by Krüppel-like factor 4 (Klf4), to prevent injury. Klf4 also regulates macrophage polarization, although the mechanisms underlying both functions are poorly understood. The aim of this study was to investigate whether and how Klf4 prevents unregulated inflammation. Methods: The bone marrow-derived macrophages and RAW264.7 cell line were used. Quantitative real-time PCR was used to determine inflammatory cytokines (IL-1β, TNF-α, IL-6 and MCP-1), Klf4 and MCPIP1 transcript levels. Extraction of nuclear and cytoplasmic proteins and Immunoblotting were used to determine Klf4, MCPIP1, relative kinases from NF-κB pathway and K63-linked polyubiquitins expression in nucleus and cytoplasm separately. Dual luciferase reporter assay was used to analyze whether Klf4 mediate MCPIP1 transcription. Immunoprecipitation was used to determine the protein interaction among Klf4, MCPIP1, TRAF6 and K63-linked polyubiquitins. Secretion of IL-1β and TNF-α into sera in mice was measured by Enzyme-linked immunosorbent assay. Results: We found that exposure to lipopolysaccharides suppresses Klf4 expression, even as it induces release of pro-inflammatory cytokines. Strikingly, Klf4 overexpression significantly lowered cytokine secretion and NF-κB signaling in the cytoplasm following exposure to lipopolysaccharide, even though Klf4 was exclusively nuclear. The cytoplasmic effects are likely mediated by MCP-1 induced protein 1 (MCPIP1), a deubiquitinase and a key modulator of inflammation that accumulates both in the nucleus and cytoplasm in response to Klf4. Indeed, binding between MCPIP1 and K63 polyubiquitins is attenuated in macrophages overexpressing Klf4, suggesting that MCPIP1 is an intermediator induced by Klf4 in the nucleus to remove K63 polyubiquitins from TRAF6 in the cytoplasm, and thereby impede NF-κB and inflammatory signaling. Importantly, Klf4 overexpression in mice alleviated sepsis symptoms following exposure to lipopolysaccharides. Conclusion: The data highlight Klf4 as an essential MCPIP1-dependent modulator of innate immunity that protects against excessive and self-destructive inflammation.

show abstract

“…In humans, type-I IFNs consist of 13 IFN-α isoforms (14 in mice), IFN-β, IFN-ε, IFN-κ, IFN-δ, and IFN-ω, which all signal through IFNAR (Kopitar-Jerala, 2017;Ng et al, 2016). As IFN-α and IFN-β are the most characterized and the most predominantly expressed type-I IFNs, we mainly discuss these two subtypes in this review.…”

Section: Ifn Families and Type-i Ifnsmentioning

confidence: 99%

“…IFNs can be classified into three families (type-I, -II, and -III) according to the protein structure and the receptors they signal through. Type-I IFNs are important immune modulator altering both innate and adaptive immunity (González-Navajas et al, 2012;Kopitar-Jerala, 2017;Trinchieri, 2010). Accumulating evidence from both human and murine studies supports their role in atherogenesis and linked clinical manifestations.…”

Section: Introductionmentioning

confidence: 99%

Type-I interferons in atherosclerosis

Chen

Tas

Winther

2019

Journal of Experimental Medicine

View full text Add to dashboard Cite

The contribution of dyslipidemia and inflammation in atherosclerosis is well established. Along with effective lipid-lowering treatments, the recent success of clinical trials with anti-inflammatory therapies and the accelerated atherosclerosis in many autoimmune diseases suggest that targeting inflammation may open new avenues for the prevention and the treatment for cardiovascular diseases (CVDs). In the past decades, studies have widened the role of type-I interferons (IFNs) in disease, from antivirus defense to autoimmune responses and immuno-metabolic syndromes. While elevated type-I IFN level in serum is associated with CVD incidence in patients with interferonopathies, experimental data have attested that type-I IFNs affect plaque-residing macrophages, potentiate foam cell and extracellular trap formation, induce endothelial dysfunction, alter the phenotypes of dendritic cells and T and B lymphocytes, and lead to exacerbated atherosclerosis outcomes. In this review, we discuss the production and the effects of type-I IFNs in different atherosclerosis-associated cell types from molecular biology studies, animal models, and clinical observations, and the potential of new therapies against type-I IFN signaling for atherosclerosis.

show abstract

The Role of Interferons in Inflammation and Inflammasome Activation

Cited by 203 publications

References 123 publications

Microglial nodules provide the environment for pathogenic T cells in human encephalitis

Microglial nodules provide the environment for pathogenic T cells in human encephalitis

Klf4 Alleviates Lipopolysaccharide-Induced Inflammation by Inducing Expression of MCP-1 Induced Protein 1 to Deubiquitinate TRAF6

Type-I interferons in atherosclerosis

Contact Info

Product

Resources

About