scholarly journals SARS-CoV-2-associated ssRNAs activate inflammation and immunity via TLR7/8

2021 ◽  
Author(s):  
Valentina Salvi ◽  
Hoang Oanh Nguyen ◽  
Francesca Sozio ◽  
Tiziana Schioppa ◽  
Mattia Laffranchi ◽  
...  
Keyword(s):  
Lung Inflammation ◽  
Viral Genome ◽  
Cytokine Production ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Dependent Lung ◽  
Molecular Patterns ◽  
Th1 Polarization ◽  
Myd88 Pathway

The inflammatory and IFN pathways of innate immunity play a key role in both resistance and pathogenesis of Coronavirus Disease 2019 (COVID-19). Innate sensors and SARS-CoV-2-Associated Molecular Patterns (SAMPs) remain to be completely defined. Here we identify single-stranded RNA (ssRNA) fragments from SARS-CoV-2 genome as direct activators of endosomal TLR7/8 and MyD88 pathway. The same sequences induced human DC activation in terms of phenotype and functions, such as IFN and cytokine production and Th1 polarization. A bioinformatic scan of the viral genome identified several hundreds of fragments potentially activating TLR7/8, suggesting that products of virus endosomal processing potently activate the IFN and inflammatory responses downstream these receptors. In vivo, SAMPs induced MyD88-dependent lung inflammation characterized by accumulation of proinflammatory and cytotoxic mediators and immune cell infiltration, as well as splenic DC phenotypical maturation. These results identify TLR7/8 as crucial cellular sensors of ssRNAs encoded by SARS-CoV-2 involved in host resistance and disease pathogenesis of COVID-19.

scholarly journals Viperin is anti-viral in vitro but is dispensable for restricting dengue virus replication or induction of innate and inflammatory responses in vivo

2021 ◽  
Vol 102 (10) ◽  
Author(s):  
Wisam-Hamzah Al Shujairi ◽  
Luke P. Kris ◽  
Kylie van der Hoek ◽  
Evangeline Cowell ◽  
Gustavo Bracho-Granado ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Denv Infection ◽  
Brain Morphology ◽  
Moderate Increase ◽  
Tnf Α ◽  
Significant Difference

Viperin has antiviral function against many viruses, including dengue virus (DENV), when studied in cells in culture. Here, the antiviral actions of viperin were defined both in vitro and in a mouse in vivo model of DENV infection. Murine embryonic fibroblasts (MEFs) derived from mice lacking viperin (vip−/−) showed enhanced DENV infection, accompanied by increased IFN-β and induction of ISGs; IFIT1 and CXCL-10 but not IRF7, when compared to wild-type (WT) MEFs. In contrast, subcutaneous challenge of immunocompetent WT and vip−/− mice with DENV did not result in enhanced infection. Intracranial infection with DENV resulted in body weight loss and neurological disease with a moderate increase in mortality in vip−/− compared with WT mice, although this was not accompanied by altered brain morphology, immune cell infiltration or DENV RNA level in the brain. Similarly, DENV induction of IFN-β, IFIT1, CXCL-10, IRF7 and TNF-α was not significantly different in WT and vip−/− mouse brain, although there was a modest but significant increase in DENV induction of IL-6 and IfI27la in the absence of viperin. NanoString nCounter analysis confirmed no significant difference in induction of a panel of inflammatory genes in WT compared to vip−/− DENV-infected mouse brains. Further, polyI:C stimulation of bone marrow-derived macrophages (BMDMs) induced TNF-α, IFN-β, IL-6 and Nos-2, but responses were not different in BMDMs generated from WT or vip−/− mice. Thus, while there is significant evidence of anti-DENV actions of viperin in some cell types in vitro, for DENV infection in vivo a lack of viperin does not affect systemic or brain susceptibility to DENV or induction of innate and inflammatory responses.

scholarly journals Resolvins as Regulators of the Immune System

2010 ◽  
Vol 10 ◽  
pp. 818-831 ◽  
Author(s):  
Hiroyuki Seki ◽  
Takaharu Sasaki ◽  
Tomomi Ueda ◽  
Makoto Arita
Keyword(s):  
Immune System ◽  
Acute Inflammation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Bioactive Metabolites ◽  
Cell Functions ◽  
First Response ◽  
Beneficial Impact

Inflammation is the first response of the immune system to infection or injury, but excessive or inappropriate inflammatory responses contribute to a range of acute and chronic human diseases. Clinical assessment of dietary supplementation of ω-3 polyunsaturated fatty acids (i.e., eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) indicate that they have beneficial impact on these diseases, although the mechanisms are poorly understood at the molecular level. In this decade, it has been revealed that EPA and DHA are enzymatically converted to bioactive metabolites in the course of acute inflammation and resolution. These metabolites were shown to regulate immune cell functions and to display potent anti-inflammatory actions bothin vitroandin vivo. Because of their ability to resolve an acute inflammatory response, they are referred to as proresolving mediators, or resolvins. In this review, we provide an overview of the formation and actions of these lipid mediators.

A dual-action peptide-containing hydrogel targets wound infection and inflammation

2020 ◽  
Vol 12 (524) ◽  
pp. eaax6601 ◽  
Author(s):  
Manoj Puthia ◽  
Marta Butrym ◽  
Jitka Petrlova ◽  
Ann-Charlotte Strömdahl ◽  
Madelene Å. Andersson ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Nuclear Factor Κb ◽  
Reporter Mice ◽  
Dual Action ◽  
Infection And Inflammation ◽  
Molecular Patterns

There is a clinical need for improved wound treatments that prevent both infection and excessive inflammation. TCP-25, a thrombin-derived peptide, is antibacterial and scavenges pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide, thereby preventing CD14 interaction and Toll-like receptor dimerization, leading to reduced downstream immune activation. Here, we describe the development of a hydrogel formulation that was functionalized with TCP-25 to target bacteria and associated PAMP-induced inflammation. In vitro studies determined the polymer prerequisites for such TCP-25–mediated dual action, favoring the use of noncharged hydrophilic hydrogels, which enabled peptide conformational changes and LPS binding. The TCP-25–functionalized hydrogels killed Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa bacteria in vitro, as well as in experimental mouse models of subcutaneous infection. The TCP-25 hydrogel also mediated reduction of LPS-induced local inflammatory responses, as demonstrated by analysis of local cytokine production and in vivo bioimaging using nuclear factor κB (NF-κB) reporter mice. In porcine partial thickness wound models, TCP-25 prevented infection with S. aureus and reduced concentrations of proinflammatory cytokines. Proteolytic fragmentation of TCP-25 in vitro yielded a series of bioactive TCP fragments that were identical or similar to those present in wounds in vivo. Together, the results demonstrate the therapeutic potential of TCP-25 hydrogel, a wound treatment based on the body’s peptide defense, for prevention of both bacterial infection and the accompanying inflammation.

scholarly journals In Vivo Targeting of CXCR4—New Horizons

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5920
Author(s):  
Margret Schottelius ◽  
Ken Herrmann ◽  
Constantin Lapa
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Clinical Status ◽  
Inflammatory Stimuli ◽  
Imaging Probes ◽  
Recent Developments ◽  
Chemokine Receptor 4

Given its pre-eminent role in the context of tumor cell growth as well as metastasis, the C-X-C motif chemokine receptor 4 (CXCR4) has attracted a lot of interest in the field of nuclear oncology, and clinical evidence on the high potential of CXCR4-targeted theranostics is constantly accumulating. Additionally, since CXCR4 also represents a key player in the orchestration of inflammatory responses to inflammatory stimuli, based on its expression on a variety of pro- and anti-inflammatory immune cells (e.g., macrophages and T-cells), CXCR4-targeted inflammation imaging has recently gained considerable attention. Therefore, after briefly summarizing the current clinical status quo of CXCR4-targeted theranostics in cancer, this review primarily focuses on imaging of a broad spectrum of inflammatory diseases via the quantification of tissue infiltration with CXCR4-expressing immune cells. An up-to-date overview of the ongoing preclinical and clinical efforts to visualize inflammation and its resolution over time is provided, and the predictive value of the CXCR4-associated imaging signal for disease outcome is discussed. Since the sensitivity and specificity of CXCR4-targeted immune cell imaging greatly relies on the availability of suitable, tailored imaging probes, recent developments in the field of CXCR4-targeted imaging agents for various applications are also addressed.

scholarly journals IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Rachel A Gottschalk ◽  
Michael G Dorrington ◽  
Bhaskar Dutta ◽  
Kathleen S Krauss ◽  
Andrew J Martins ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Type I ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Gram Negative

Despite existing evidence for tuning of innate immunity to different classes of bacteria, the molecular mechanisms used by macrophages to tailor inflammatory responses to specific pathogens remain incompletely defined. By stimulating mouse macrophages with a titration matrix of TLR ligand pairs, we identified distinct stimulus requirements for activating and inhibitory events that evoked diverse cytokine production dynamics. These regulatory events were linked to patterns of inflammatory responses that distinguished between Gram-positive and Gram-negative bacteria, both in vitro and after in vivo lung infection. Stimulation beyond a TLR4 threshold and Gram-negative bacteria-induced responses were characterized by a rapid type I IFN-dependent decline in inflammatory cytokine production, independent of IL-10, whereas inflammatory responses to Gram-positive species were more sustained due to the absence of this IFN-dependent regulation. Thus, disparate triggering of a cytokine negative feedback loop promotes tuning of macrophage responses in a bacteria class-specific manner and provides context-dependent regulation of inflammation dynamics.

scholarly journals Cannabinoid type 2 receptor (CB2R) distribution in dermatomyositis skin and peripheral blood mononuclear cells (PBMCs) and in vivo effects of LenabasumTM

2022 ◽  
Vol 24 (1) ◽  
Author(s):  
Spandana Maddukuri ◽  
Jay Patel ◽  
De Anna Diaz ◽  
Kristen L. Chen ◽  
Maria Wysocka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Immune Cell ◽  
Cell Populations ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Ifn Γ

Abstract Background Lenabasum is a cannabinoid type 2 receptor (CB2R) reverse agonist that demonstrates anti-inflammatory effects in vivo and in vitro in dermatomyositis (DM) and is currently being investigated for therapeutic potential. The purpose of our study is to investigate CB2R distribution as well as the effects of lenabasum in DM. Methods Immunohistochemistry staining (IHC) was utilized to examine immune cell and cytokine production changes in lesional DM skin biopsies from lenabasum and placebo-treated patients. CB2R expression in various immune cell populations within DM skin was investigated with image mass cytometry (IMC), whereas flow cytometry elucidated CB2R expression in DM peripheral blood mononuclear cells (PBMCs) as well as cytokine production by CB2R-expressing cell populations. Results After 12 weeks of lenabasum treatment, IHC staining showed that CD4+ T cells, CB2R, IL-31, IFN-γ, and IFN-β cytokines were downregulated. IFN-γ and IFN-β mRNA decreased in lesional DM skin but not in PBMCs. IMC findings revealed that CB2R was upregulated in DM lesional skin compared to HC skin and DM PBMCs (p<0.05). In DM skin, CB2R was upregulated on dendritic cells, B cells, T cells, and macrophages while dendritic cells had the greatest expression in both DM skin and PBMCs (p<0.05). These CB2R+ cells in the skin produce IL-31, IL-4, IFN-γ, and IFN-β. Conclusion Our findings of differential CB2R expression based on location and cell type suggest modes by which lenabasum may exert anti-inflammatory effects in DM and highlights dendritic cells as potential therapeutic targets.

Ubiquitin-Conjugating Enzyme Ubc13 Is a Critical Component of TRAF-Mediated Inflammatory Responses.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1136-1136
Author(s):  
Toru Fukushima ◽  
Shu-ichi Matsuzawa ◽  
Christinia L. Kress ◽  
Jean Marie Bruey ◽  
Maryla Krajewska ◽  
...  
Keyword(s):  
Immune Cell ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Adapter Proteins ◽  
Gene Ablation ◽  
Dependent Signal ◽  
Ubiquitin Conjugating Enzyme ◽  
Family Cytokine ◽  
Conjugating Enzyme

Abstract Ubc13 is an ubiquitin-conjugating enzyme responsible for non-canonical ubiquitination of TRAF-family adapter proteins involved in Toll-like Receptor (TLR) and TNF-family cytokine receptor signaling. Gene ablation was used to study the function of Ubc13 in mice. While homozygous ubc13 gene disruption resulted in embryonic lethality, heterozygous ubc13+/− mice appeared normal without alterations in immune cell populations. Haploinsufficient ubc13+/− mice were resistant to lipopolysaccharide (LPS)-induced lethality, and demonstrated reduced in vivo ubiquitination of TRAF6. Macrophages and splenocytes isolated from ubc13+/− mice exhibited reduced LPS-inducible cytokine secretion and impaired activation of TRAF-dependent signal transduction pathways (NF-kB, JNK, p38 MAPK). These findings document a critical role for Ubc13 in inflammatory responses, and suggest that agents reducing Ubc13 activity could have therapeutic utility.

scholarly journals Anti-Inflammatory and Immunosuppressive Effects of the A2AAdenosine Receptor

2011 ◽  
Vol 11 ◽  
pp. 320-339 ◽  
Author(s):  
Gillian R. Milne ◽  
Timothy M. Palmer
Keyword(s):  
Molecular Mechanisms ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Current Evidence ◽  
Receptor Subtypes ◽  
Protective Effects ◽  
Stress Injury ◽  
Anti Inflammatory

The production of adenosine represents a critical endogenous mechanism for regulating immune and inflammatory responses during conditions of stress, injury, or infection. Adenosine exerts predominantly protective effects through activation of four 7-transmembrane receptor subtypes termed A1, A2A, A2B, and A3, of which the A2Aadenosine receptor (A2AAR) is recognised as a major mediator of anti-inflammatory responses. The A2AAR is widely expressed on cells of the immune system and numerousin vitrostudies have identified its role in suppressing key stages of the inflammatory process, including leukocyte recruitment, phagocytosis, cytokine production, and immune cell proliferation. The majority of actions produced by A2AAR activation appear to be mediated by cAMP, but downstream events have not yet been well characterised. In this article, we review the current evidence for the anti-inflammatory effects of the A2AAR in different cell types and discuss possible molecular mechanisms mediating these effects, including the potential for generalised suppression of inflammatory gene expression through inhibition of the NF-κB and JAK/STAT proinflammatory signalling pathways. We also evaluate findings fromin vivostudies investigating the role of the A2AAR in different tissues in animal models of inflammatory disease and briefly discuss the potential for development of selective A2AAR agonists for use in the clinic to treat specific inflammatory conditions.

scholarly journals Toll-Like Receptor 9-Mediated Inflammation Triggers Alveolar Bone Loss in Experimental Murine Periodontitis

2015 ◽  
Vol 83 (7) ◽  
pp. 2992-3002 ◽  
Author(s):  
Paul D. Kim ◽  
Xia Xia-Juan ◽  
Katie E. Crump ◽  
Toshiharu Abe ◽  
George Hajishengallis ◽  
...  
Keyword(s):  
Bone Loss ◽  
Cytokine Production ◽  
Alveolar Bone ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Extracellular Dna ◽  
Toll Like Receptor ◽  
Content Type ◽  
Periodontal Inflammation

Chronic periodontitis is a local inflammatory disease induced by a dysbiotic microbiota and leading to destruction of the tooth-supporting structures. Microbial nucleic acids are abundantly present in the periodontium, derived through release after phagocytic uptake of microbes and/or from biofilm-associated extracellular DNA. Binding of microbial DNA to its cognate receptors, such as Toll-like receptor 9 (TLR9), can trigger inflammation. In this study, we utilized TLR9 knockout (TLR9−/−) mice and wild-type (WT) controls in a murine model ofPorphyromonas gingivalis-induced periodontitis and report the firstin vivoevidence that TLR9 signaling mediates the induction of periodontal bone loss.P. gingivalis-infected WT mice exhibited significantly increased bone loss compared to that in sham-infected WT mice orP. gingivalis-infected TLR9−/−mice, which were resistant to bone loss. Consistent with this, the expression levels of interleukin 6 (IL-6), tumor necrosis factor (TNF), and receptor-activator of nuclear factor kappa B ligand (RANKL) were significantly elevated in the gingival tissues of the infected WT mice but not in infected TLR9−/−mice compared to their levels in controls.Ex vivostudies using splenocytes and bone marrow-derived macrophages revealed significantly diminished cytokine production in TLR9−/−cells relative to the cytokine production in WT cells in response toP. gingivalis, thereby implicating TLR9 in inflammatory responses to this organism. Intriguingly, compared to the cytokine production in WT cells, TLR9−/−cells exhibited significantly decreased proinflammatory cytokine production upon challenge with lipopolysaccharide (LPS) (TLR4 agonist) or Pam3Cys (TLR2 agonist), suggesting possible cross talk between TLR9, TLR4, and TLR2. Collectively, our results provide the first proof-of-concept evidence implicating TLR9-triggered inflammation in periodontal disease pathogenesis, thereby identifying a new potential therapeutic target to control periodontal inflammation.

scholarly journals Cholesterol-modifying drugs in COVID-19

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Nathalie M Schmidt ◽  
Peter A C Wing ◽  
Jane A McKeating ◽  
Mala K Maini
Keyword(s):  
Immune Cell ◽  
Inflammatory Responses ◽  
The Elderly ◽  
Virus Infectivity ◽  
In Vivo Models ◽  
Virus Particles ◽  
Enveloped Virus ◽  
Poor Outcomes

Abstract Infection with severe acute respiratory syndrom coronavirus 2 (SARS-CoV-2) is more likely to lead to poor outcomes in the elderly and those with cardiovascular disease, obesity or metabolic syndrome. Here, we consider mechanisms by which dyslipidaemia and the use of cholesterol-modifying drugs could influence the virus–host relationship. Cholesterol is essential for the assembly, replication and infectivity of enveloped virus particles; we highlight several cholesterol-modifying drugs with the potential to alter the SARS-CoV-2 life cycle that could be tested in in vitro and in vivo models. Although cholesterol is an essential component of immune cell membranes, excess levels can dysregulate protective immunity and promote exaggerated pulmonary and systemic inflammatory responses. Statins block the production of multiple sterols, oxysterols and isoprenoids, resulting in a pleiotropic range of context-dependent effects on virus infectivity, immunity and inflammation. We highlight antiviral, immunomodulatory and anti-inflammatory effects of cholesterol-modifying drugs that merit further consideration in the management of SARS-CoV-2 infection.

Sign in / Sign up

Export Citation Format

Share Document