scholarly journals The Threshold Effect: Lipopolysaccharide-Induced Inflammatory Responses in Primary Macrophages Are Differentially Regulated in an iRhom2-Dependent Manner

2021 ◽  
Vol 10 ◽  
Author(s):  
Joseph Skurski ◽  
Garima Dixit ◽  
Carl P. Blobel ◽  
Priya D. Issuree ◽  
Thorsten Maretzky
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Immune Cells ◽  
Regulatory Mechanism ◽  
Inflammatory Responses ◽  
Genetic Model ◽  
Innate Immune ◽  
High Dose ◽  
Dependent Manner ◽  
Low Levels

A well-controlled innate immune response is characterized by a rapid yet self-limiting inflammatory response. Although much is known about the range of inflammatory stimuli capable of triggering an innate immune response, the mechanisms which govern the degree of inflammation induced by inflammatory insults and the mechanisms in place to reset or maintain homeostasis are poorly understood. Tumor necrosis factor (TNF) is a potent early response pro-inflammatory cytokine produced by immune cells following a broad range of insults spanning autoimmunity and metabolic diseases to pathogenic infections. Previous studies have shown that a disintegrin and metalloproteinase (ADAM) 17 controls the release of soluble TNF and epidermal growth factor receptor signaling. Utilizing a genetic model of ADAM17 deficiency through the deletion of its regulator, the inactive rhomboid 2 (iRhom2), we show that loss of ADAM17 activity in innate immune cells leads to decreased expression of various cytokines in response to low levels of pathogen-associated molecular pattern (PAMP) stimulation but not at high-dose stimulation. In addition, TNF receptor (TNFR) 1/2-deficient bone marrow-derived macrophages yielded significantly reduced TNF expression following low levels of PAMP stimulation, suggesting that signaling through the TNFRs in immune cells drives a feed-forward regulatory mechanism wherein low levels of TNF allow sustained enhancement of TNF expression in an iRhom2/ADAM17-dependent manner. Thus, we demonstrate that inflammatory expression of TNF and IL1β is differentially regulated following high or low doses of PAMP stimulation, invoking the activation of a previously unknown regulatory mechanism of inflammation.

Differential modulation of innate immune response by epinephrine and estradiol

2017 ◽  
Vol 30 (3) ◽  
Author(s):  
Sona Margaryan ◽  
Armenuhi Hyusyan ◽  
Anush Martirosyan ◽  
Shushan Sargsian ◽  
Gayane Manukyan
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Dependent Manner ◽  
Induced Expression ◽  
Short Term Exposure ◽  
Tnf Α ◽  
Vitro Effect ◽  
Dose Dependent

AbstractBackgroundAlthough it is widely accepted that catecholamines and estrogens influence immunity and have consequences for health, their effect on innate immunity (e.g. monocytes and neutrophils) is still not fully investigated.Materials and methodsOur study aimed to analyze the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, monocyte chemoattractant protein (MCP)-1 and IL-8 by whole blood cells following short-term exposure to epinephrine (Epi) and 17β-estradiol (E2) in the presence or absence of lipopolysaccharide (LPS). We also evaluated the in vitro effect of these hormones on expression of β2 integrin (CD11b/CD18) and L-selectin (CD62L) by circulating neutrophils and monocytes in the blood of healthy subjects.ResultsEpi has shown a potential to modulate the production of pro-inflammatory mediators. Its exposure resulted in significantly increased production of IL-8 in a dose-dependent manner. On the contrary, a dose-dependent suppression of LPS-induced production of IL-1β, IL-8, and MCP-1 by Epi was observed. In neutrophils, a modest rise in CD11b expression was observed after Epi exposure. Simultaneously, Epi suppressed LPS-induced expression of CD11b and CD18. In monocytes, Epi suppressed LPS-induced expression of C11b. E2 inhibited LPS-induced TNF-α production and caused a significant decrease in CD62L expression in both cell populations. No significant changes were observed after double exposure of cells with Epi and E2.ConclusionsThus, our results show that Epi and E2 differentially modulate the innate immune response and have a dual effect on cytokine modulation. The findings suggest that the observed immunoregulatory role of Epi and E2 may influence the outcome in endotoxin responses and can be critical in the regulation of inflammatory responses.

scholarly journals microRNA-210 and microRNA-3570 Negatively Regulate NF-κB-Mediated Inflammatory Responses by Targeting RIPK2 in Teleost Fish

2021 ◽  
Vol 12 ◽  
Author(s):  
Hui Su ◽  
Renjie Chang ◽  
Weiwei Zheng ◽  
Yuena Sun ◽  
Tianjun Xu
Keyword(s):  
Immune Response ◽  
Signaling Pathway ◽  
Innate Immune Response ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Regulatory Role ◽  
Inflammatory Cytokine Production ◽  
Immune Genes ◽  
Lower Vertebrates ◽  
Antimicrobial Immunity

Pathogen infection can cause the production of inflammatory cytokines, which are key mediators that cause the host’s innate immune response. Therefore, proper regulation of immune genes associated with inflammation is essential for immune response. Among them, microRNAs (miRNAs) as gene regulator have been widely reported to be involved in the innate immune response of mammals. However, the regulatory network in which miRNAs are involved in the development of inflammation is largely unknown in lower vertebrates. Here, we identified two miRNAs from miiuy croaker (Miichthys miiuy), miR-210 and miR-3570, which play a negative regulatory role in host antibacterial immunity. We found that the expressions of miR-210 and miR-3570 were significantly upregulated under the stimulation of Gram-negative bacterium vibrio harveyi and LPS (lipopolysaccharide). Induced miR-210 and miR-3570 inhibit inflammatory cytokine production by targeting RIPK2, thereby avoiding excessive inflammation. In particular, we found that miR-210 and miR-3570 negatively regulate antimicrobial immunity by regulating the RIPK2-mediated NF-κB signaling pathway. The collective results indicated that both miRNAs are used as negative feedback regulators to regulate RIPK2-mediated NF-κB signaling pathway and thus play a regulatory role in bacteria-induced inflammatory response.

scholarly journals The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression

Oncogene ◽  
2020 ◽  
Vol 39 (44) ◽  
pp. 6841-6855 ◽  
Author(s):  
Christina Jessen ◽  
Julia K. C. Kreß ◽  
Apoorva Baluapuri ◽  
Anita Hufnagel ◽  
Werner Schmitz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Transcription Factor ◽  
Prostaglandin E2 ◽  
Innate Immune Response ◽  
Stress Responses ◽  
Melanoma Cells ◽  
Innate Immune ◽  
Dependent Manner

AbstractThe transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H2O2 or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.

scholarly journals TRAF6 and TAK1 contribute to SAMHD1-mediated negative regulation of NF-κB signaling

2020 ◽  
Author(s):  
Constanza E. Espada ◽  
Corine St. Gelais ◽  
Serena Bonifati ◽  
Victoria V. Maksimova ◽  
Michael P. Cahill ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Transforming Growth Factor ◽  
Negative Regulation ◽  
Innate Immune ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Intracellular Dntp ◽  
Hiv 1

Sterile alpha motif and HD-domain-containing protein 1 (SAMHD1) restricts HIV-1 replication by limiting the intracellular dNTP pool. SAMHD1 also suppresses the activation of NF-κB in response to viral infections and inflammatory stimuli. However, the mechanisms by which SAMHD1 negatively regulates this pathway remain unclear. Here we show that SAMHD1-mediated suppression of NF-κB activation is modulated by two key mediators of NF-κB signaling, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and transforming growth factor-ß-activated kinase-1 (TAK1). We compared NF-κB activation stimulated by interleukin (IL)-1ß in monocytic THP-1 control and SAMHD1 knockout (KO) cells with and without partial TRAF6 knockdown (KD), or in cells treated with TAK1 inhibitors. Relative to control cells, IL-1ß-treated SAMHD1 KO cells showed increased phosphorylation of the inhibitor of NF-κB (IκBα), an indication of pathway activation, and elevated levels of TNF-α mRNA. Moreover, SAMHD1 KO combined with TRAF6 KD or pharmacological TAK1 inhibition reduced IκBα phosphorylation and TNF-α mRNA to the level of control cells. SAMHD1 KO cells infected with single-cycle HIV-1 showed elevated infection and TNF-α mRNA levels compared to control cells, and the effects were significantly reduced by TRAF6 KD or TAK1 inhibition. We further demonstrated that overexpressed SAMHD1 inhibited TRAF6-stimulated NF-κB reporter activity in HEK293T cells in a dose-dependent manner. SAMHD1 contains a nuclear localization signal (NLS), but an NLS-defective SAMHD1 exhibited a suppressive effect similar to the wild-type protein. Our data suggest that the TRAF6-TAK1 axis contributes to SAMHD1-mediated suppression of NF-κB activation and HIV-1 infection. Importance Cells respond to pathogen infection by activating a complex innate immune signaling pathway, which culminates in the activation of transcription factors and secretion of a family of functionally and genetically related cytokines. However, excessive immune activation may cause tissue damage and detrimental effects on the host. Therefore, in order to maintain host homeostasis, the innate immune response is tightly regulated during viral infection. We have reported SAMHD1 as a novel negative regulator of the innate immune response. Here, we provide new insights into SAMHD1-mediated negative regulation of the NF-κB pathway at the TRAF6-TAK1 checkpoint. We show that SAMHD1 inhibits TAK1 activation and TRAF6 signaling in response to proinflammatory stimuli. Interestingly, TRAF6 knockdown in SAMHD1-deficient cells significantly inhibited HIV-1 infection and activation of NF-κB induced by virus infection. Our research reveals a new negative regulatory mechanism by which SAMHD1 participates in the maintenance of cellular homeostasis during HIV-1 infection and inflammation.

scholarly journals Promotion of Colonization and Virulence by Cholera Toxin Is Dependent on Neutrophils

2013 ◽  
Vol 81 (9) ◽  
pp. 3338-3345 ◽  
Author(s):  
Jessica Queen ◽  
Karla J. F. Satchell
Keyword(s):  
Immune Response ◽  
Cholera Toxin ◽  
Innate Immune Response ◽  
Host Response ◽  
Survival Rates ◽  
Innate Immune ◽  
Infection Model ◽  
High Dose ◽  
Content Type ◽  
Inflammatory Protein

ABSTRACTThe innate immune response toVibrio choleraeinfection is poorly understood, but this knowledge is critical for the design of safe, effective vaccines. Using an adult mouse intestinal infection model, this study examines the contribution of neutrophils to host immunity, as well as the effect of cholera toxin and other secreted factors on this response. Depletion of neutrophils from mice with anti-Ly6G IA8 monoclonal antibody led to similar survival rates of mice infected with low or moderate doses of toxigenicV. choleraeEl Tor O1. At a high dose, neutropenic mice showed increased rates of survival compared to neutrophil-replete animals. Expression of cholera toxin was found to be protective to the neutropenic host, and this phenotype can be replicated by the administration of purified toxin. Neutrophils do not effectively clear colonizing bacteria from the small intestine, nor do they alter induction of early immune-modulating signals. In both neutropenic and neutrophil-replete animals, the local response to infection is characterized by expression of interleukin 6 (IL-6), IL-10, and macrophage inflammatory protein 2 alpha (MIP-2). Overall, these data indicate that the innate immune response to toxigenicV. choleraeinfection differs dramatically from the host response to nontoxigenic infection or vaccination, where neutrophils are protective to the host. In the absence of neutrophils, cholera toxin induces immunomodulatory effects that increase host survival. In cholera toxin-producing strains, similar to nontoxigenic infection, accessory toxins are critical to virulence, indicating that cholera toxin and the other secreted toxins modulate the host response by different mechanisms, with both contributing to bacterial persistence and virulence.

scholarly journals A Chemokine-Degrading Extracellular Protease Made by Group A Streptococcus Alters Pathogenesis by Enhancing Evasion of the Innate Immune Response

2008 ◽  
Vol 76 (3) ◽  
pp. 978-985 ◽  
Author(s):  
Paul Sumby ◽  
Shizhen Zhang ◽  
Adeline R. Whitney ◽  
Fabiana Falugi ◽  
Guido Grandi ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Group A Streptococcus ◽  
Cell Envelope ◽  
Innate Immune ◽  
Infection Model ◽  
Dependent Manner ◽  
Wild Type ◽  
Group A

ABSTRACT Circumvention of the host innate immune response is critical for bacterial pathogens to infect and cause disease. Here we demonstrate that the group A Streptococcus (GAS; Streptococcus pyogenes) protease SpyCEP (S. pyogenes cell envelope protease) cleaves granulocyte chemotactic protein 2 (GCP-2) and growth-related oncogene alpha (GROα), two potent chemokines made abundantly in human tonsils. Cleavage of GCP-2 and GROα by SpyCEP abrogated their abilities to prime neutrophils for activation, detrimentally altering the innate immune response. SpyCEP expression is negatively regulated by the signal transduction system CovR/S. Purified recombinant CovR bound the spyCEP gene promoter region in vitro, indicating direct regulation. Immunoreactive SpyCEP protein was present in the culture supernatants of covR/S mutant GAS strains but not in supernatants from wild-type strains. However, wild-type GAS strains do express SpyCEP, where it is localized to the cell wall. Strain MGAS2221, an organism representative of the highly virulent and globally disseminated M1T1 GAS clone, differed significantly from its isogenic spyCEP mutant derivative strain in a mouse soft tissue infection model. Interestingly, and in contrast to previous studies, the isogenic mutant strain generated lesions of larger size than those formed following infection with the parent strain. The data indicate that SpyCEP contributes to GAS virulence in a strain- and disease-dependent manner.

scholarly journals Yolkin Isolated from Hen Egg Yolk as a Natural Immunoregulator, Activating Innate Immune Response in BMDM Macrophages

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
W. Kazana ◽  
M. Mitkiewicz ◽  
M. Ochnik ◽  
M. Sochocka ◽  
A. Zambrowicz ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Innate Immune Response ◽  
Egg Yolk ◽  
The Body ◽  
Innate Immune ◽  
Type I ◽  
Dependent Manner ◽  
Hen Egg Yolk ◽  
Hen Egg

One of the goals of biomedical sciences is to search and identify natural compounds that are safe, have no side effects, and possess immunostimulatory activity. It has been proven that medicines of natural origin can be effective agents, supporting the therapy of many diseases, not only in the weakened immune system of the body but also in the prevention of many diseases in healthy people. It has been shown that yolkin, a polypeptide complex isolated from hen egg yolk as a fraction accompanying immunoglobulin Y (IgY), possesses potential biological activity. However, the mechanism of its action has not been explained. The objective of this investigation was to examine the molecular mechanisms of innate immune response, activated in response to yolkin, in murine bone marrow-derived macrophages (BMDM). It was shown that yolkin induced phosphorylation of extracellular signal-kinases (ERK1/2) and c-Jun N-terminal kinase (JNK) and upregulated expression and production of type I interferons, TNF-α (tumor necrosis factor α), and nitric oxide (NO), in BMDM cells. Using pharmacological inhibitors of ERK 1/2 and JNK kinases, we revealed that the JNK signaling cascade is required for yolkin-induced inducible NOS expression and upregulation of NO production in mouse macrophages. Using the TLR4-deficient BMDM cell line, we established that yolkin can activate macrophages in a TLR4-dependent manner. It was also shown that NO, TNF-α, and type I IFNs (α/β) produced by BMDM cells in response to yolkin triggered antiviral activity. These data indicate that yolkin affects the regulation of the immune system and antiviral response; therefore, it can be used as an effective immunostimulator of the innate immunity or as a supplement of the conventional therapy of immunodeficiency.

scholarly journals Cathelicidin, vitamin D3 dan imunitas terhadap tuberkulosis

2020 ◽  
Vol 20 (3) ◽  
Author(s):  
Yunita Arliny ◽  
Maryatun Hasan
Keyword(s):  
Vitamin D ◽  
Immune Response ◽  
Innate Immune Response ◽  
Vitamin D3 ◽  
Immune Cells ◽  
Active Form ◽  
Innate Immune ◽  
Dihydroxyvitamin D3 ◽  
1,25 Dihydroxyvitamin D3 ◽  
Natural Defense

Abstrak. Tuberkulosis (TB) merupakan salah satu penyakit infeksi yang menjadi masalah di dunia. Risiko untuk mendapatkan infeksi TB dipengaruhi oleh imunitas alamiah melawan mikobakteria. Peptida antimikroba merupakan salah satu barrier pertahanan alamiah. Cathelicidin adalah suatu peptida anti mikroba yang berperan pada proses imunitas terhadap TB. Cathelicidin Leusin Leusin-37 (LL-37) merupakan satu-satunya cathelicidin yang ada pada manusia dan dapat diekspresikan dari beberapa sel temasuk sel imun. Inducer Cathelicidin yang paling poten adalah 1,25-dihydroxyvitamin D3 yang merupakan bentuk aktif vitamin D 25(OH)D3. Tinjauan pustaka ini membahas tentang cathelicidin, vitamin D3 dam peranannya pada imunitas terhadap TB.Kata kunci: Cathelicidin, 1,25-dihydroxyvitamin D3, vitamin D 25(OH)2D3, imunitas, TuberkulosisAbstract. Tuberculosis is one of the most important infectious diseases worldwide. The susceptibility to this disease depends to great extent on the innate immune response against mycobacteria. Antimicrobial peptides are one of the natural defense barriers. Cathelicidin Leucine Leucine-37 (LL-37) is the only cathelicidin present in humans and synthesized by several cells including immune cells. The most effective inducer of Cathelicidin is 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3), which is an active form of vitamin D 25(OH)D3. This review discusses cathelicidin, vitamin D3 and its role in immunity against TBKeywords: Cathelicidin, 1,25-dihydroxyvitamin D3, vitamin D 25(OH)D3, immunity, Tuberkulosis

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