Exposure of Microglia to Interleukin-4 Represses NF-κB-Dependent Transcription of Toll-Like Receptor-Induced Cytokines

Interleukin (IL)-4 is a cytokine that affects both adaptive and innate immune responses. In the central nervous system, microglia express IL-4 receptors and it has been described that IL-4-exposed microglia acquire anti-inflammatory properties. We here demonstrate that IL-4 exposure induces changes in the cell surface protein expression profile of primary rhesus macaque microglia and enhances their potential to induce proliferation of T cells with a regulatory signature. Moreover, we show that Toll like receptor (TLR)-induced cytokine production is broadly impaired in IL-4-exposed microglia at the transcriptional level. IL-4 type 2 receptor-mediated signaling is shown to be crucial for the inhibition of microglial innate immune responses. TLR-induced nuclear translocalization of NF-κB appeared intact, and we found no evidence for epigenetic modulation of target genes. By contrast, nuclear extracts from IL-4-exposed microglia contained significantly less NF-κB capable of binding to its DNA consensus site. Further identification of the molecular mechanisms that underlie the inhibition of TLR-induced responses in IL-4-exposed microglia may aid the design of strategies that aim to modulate innate immune responses in the brain, for example in gliomas.

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Faculty Opinions recommendation of Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1123124.580249 ◽

2008 ◽

Author(s):

Joseph Mizgerd

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Innate Immune Responses ◽

Toll Like Receptor

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MicroRNAs from Snellenius manilae bracovirus regulate innate and cellular immune responses of its host Spodoptera litura

Communications Biology ◽

10.1038/s42003-020-01563-3 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Cheng-Kang Tang ◽

Chih-Hsuan Tsai ◽

Carol-P. Wu ◽

Yu-Hsien Lin ◽

Sung-Chan Wei ◽

...

Keyword(s):

Immune Responses ◽

Spodoptera Litura ◽

Molecular Mechanisms ◽

Innate Immune ◽

Sequencing Analysis ◽

Innate Immune Responses ◽

Cellular Immune Responses ◽

Next Generation Sequencing Analysis ◽

Cellular Immune ◽

Generation Sequencing

AbstractTo avoid inducing immune and physiological responses in insect hosts, parasitoid wasps have developed several mechanisms to inhibit them during parasitism, including the production of venom, specialized wasp cells, and symbioses with polydnaviruses (PDVs). These mechanisms alter the host physiology to give the wasp offspring a greater chance of survival. However, the molecular mechanisms for most of these alterations remain unclear. In the present study, we applied next-generation sequencing analysis and identified several miRNAs that were encoded in the genome of Snellenius manilae bracovirus (SmBV), and expressed in the host larvae, Spodoptera litura, during parasitism. Among these miRNAs, SmBV-miR-199b-5p and SmBV-miR-2989 were found to target domeless and toll-7 in the host, which are involved in the host innate immune responses. Microinjecting the inhibitors of these two miRNAs into parasitized S. litura larvae not only severely decreased the pupation rate of Snellenius manilae, but also restored the phagocytosis and encapsulation activity of the hemocytes. The results demonstrate that these two SmBV-encoded miRNAs play an important role in suppressing the immune responses of parasitized hosts. Overall, our study uncovers the functions of two SmBV-encoded miRNAs in regulating the host innate immune responses upon wasp parasitism.

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Innate immune responses to toll-like receptor stimulation are altered during the course of pregnancy

Journal of Reproductive Immunology ◽

10.1016/j.jri.2018.05.009 ◽

2018 ◽

Vol 128 ◽

pp. 30-37 ◽

Cited By ~ 14

Author(s):

Susanne Maria Ziegler ◽

Cai Niklaas Feldmann ◽

Sven Hendrik Hagen ◽

Laura Richert ◽

Tanja Barkhausen ◽

...

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Innate Immune Responses ◽

Toll Like Receptor ◽

Receptor Stimulation

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Toll-Like Receptor-Triggered Calcium Mobilization Protects Mice against Bacterial Infection through Extracellular ATP Release

Infection and Immunity ◽

10.1128/iai.02546-14 ◽

2014 ◽

Vol 82 (12) ◽

pp. 5076-5085 ◽

Cited By ~ 29

Author(s):

Hua Ren ◽

Yunfei Teng ◽

Binghe Tan ◽

Xiaoyu Zhang ◽

Wei Jiang ◽

...

Keyword(s):

Immune Responses ◽

Pyridoxal Phosphate ◽

Atp Release ◽

Extracellular Atp ◽

Calcium Mobilization ◽

Innate Immune ◽

Disulfonic Acid ◽

Dependent Manner ◽

Innate Immune Responses ◽

Toll Like Receptor

ABSTRACTExtracellular ATP (eATP), released as a “danger signal” by injured or stressed cells, plays an important role in the regulation of immune responses, but the relationship between ATP release and innate immune responses is still uncertain. In this study, we demonstrated that ATP was released through Toll-like receptor (TLR)-associated signaling in bothEscherichia coli-infected mice and lipopolysaccharide (LPS)- or Pam3CSK4-treated macrophages. This ATP release could be blocked completely only byN-ethylmaleimide (NEM), not by carbenoxolone (CBX), flufenamic acid (FFA), or probenecid, suggesting the key role of exocytosis in this process. Furthermore, LPS-induced ATP release could also be reduced dramatically through suppressing calcium mobilization by use of U73122, caffeine, and thapsigargin (TG). In addition, the secretion of interleukin-1β (IL-1β) and CCL-2 was enhanced significantly by ATP, in a time- and dose-dependent manner. Meanwhile, macrophage-mediated phagocytosis of bacteria was also promoted significantly by ATP stimulation. Furthermore, extracellular ATP reduced the number of invading bacteria and protected mice from peritonitis by activating purinergic receptors. Mechanistically, phosphorylation of AKT and ERK was overtly increased by ATP in antibacterial immune responses. Accordingly, if we blocked the P2X- and P2Y-associated signaling pathway by using suramin and pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid), tetrasodium salt (PPADS), the ATP-enhanced immune response was restrained significantly. Taken together, our findings reveal an internal relationship between danger signals and TLR signaling in innate immune responses, which suggests a potential therapeutic significance of calcium mobilization-mediated ATP release in infectious diseases.

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Integrative Transcriptomics Reveals Activation of Innate Immune Responses and Inhibition of Inflammation During Oral Immunotherapy for Egg Allergy in Children

Frontiers in Immunology ◽

10.3389/fimmu.2021.704633 ◽

2021 ◽

Vol 12 ◽

Author(s):

Piia Karisola ◽

Kati Palosuo ◽

Victoria Hinkkanen ◽

Lukas Wisgrill ◽

Terhi Savinko ◽

...

Keyword(s):

Gene Expression ◽

Clinical Outcome ◽

Immune Responses ◽

Molecular Mechanisms ◽

Expression Patterns ◽

Oral Immunotherapy ◽

Innate Immune ◽

Egg Allergy ◽

Innate Immune Responses ◽

Open Label

We previously reported the results of a randomized, open-label trial of egg oral immunotherapy (OIT) in 50 children where 44% were desensitized and 46% were partially desensitized after 8 months of treatment. Here we focus on cell-mediated molecular mechanisms driving desensitization during egg OIT. We sought to determine whether changes in genome-wide gene expression in blood cells during egg OIT correlate with humoral responses and the clinical outcome. The blood cell transcriptome of 50 children receiving egg OIT was profiled using peripheral blood mononuclear cell (PBMC) samples obtained at baseline and after 3 and 8 months of OIT. We identified 467 differentially expressed genes (DEGs) after 3 or 8 months of egg OIT. At 8 months, 86% of the DEGs were downregulated and played a role in the signaling of TREM1, IL-6, and IL-17. In correlation analyses, Gal d 1–4-specific IgG4 antibodies associated positively with DEGs playing a role in pathogen recognition and antigen presentation and negatively with DEGs playing a role in the signaling of IL-10, IL-6, and IL-17. Desensitized and partially desensitized patients had differences in their antibody responses, and although most of the transcriptomic changes were shared, both groups had also specific patterns, which suggest slower changes in partially desensitized and activation of NK cells in the desensitized group. OIT for egg allergy in children inhibits inflammation and activates innate immune responses regardless of the clinical outcome at 8 months. Changes in gene expression patterns first appear as posttranslational protein modifications, followed by more sustained epigenetic gene regulatory functions related to successful desensitization.

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Toll-like Receptor 7 Contributes to Inflammation, Organ Injury, and Mortality in Murine Sepsis

Anesthesiology ◽

10.1097/aln.0000000000002706 ◽

2019 ◽

Vol 131 (1) ◽

pp. 105-118 ◽

Cited By ~ 3

Author(s):

Wenling Jian ◽

Lili Gu ◽

Brittney Williams ◽

Yan Feng ◽

Wei Chao ◽

...

Keyword(s):

Acute Kidney Injury ◽

Immune Responses ◽

Knockout Mice ◽

Cecal Ligation ◽

Kidney Injury ◽

Innate Immune ◽

Organ Injury ◽

Innate Immune Responses ◽

Toll Like Receptor ◽

Wild Type

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Sepsis remains a critical illness with high mortality. The authors have recently reported that mouse plasma RNA concentrations are markedly increased during sepsis and closely associated with its severity. Toll-like receptor 7, originally identified as the sensor for single-stranded RNA virus, also mediates host extracellular RNA-induced innate immune responses in vitro and in vivo. Here, the authors hypothesize that innate immune signaling via Toll-like receptor 7 contributes to inflammatory response, organ injury, and mortality during polymicrobial sepsis. Methods Sepsis was created by (1) cecal ligation and puncture or (2) stool slurry peritoneal injection. Wild-type and Toll-like receptor 7 knockout mice, both in C57BL/6J background, were used. The following endpoints were measured: mortality, acute kidney injury biomarkers, plasma and peritoneal cytokines, blood bacterial loading, peritoneal leukocyte counts, and neutrophil phagocytic function. Results The 11-day overall mortality was 81% in wild-type mice and 48% in Toll-like receptor 7 knockout mice after cecal ligation and puncture (N = 27 per group, P = 0.0031). Compared with wild-type septic mice, Toll-like receptor 7 knockout septic mice also had lower sepsis severity, attenuated plasma cytokine storm (wild-type vs. Toll-like receptor 7 knockout, interleukin-6: 43.2 [24.5, 162.7] vs. 4.4 [3.1, 12.0] ng/ml, P = 0.003) and peritoneal inflammation, alleviated acute kidney injury (wild-type vs. Toll-like receptor 7 knockout, neutrophil gelatinase-associated lipocalin: 307 ± 184 vs.139 ± 41-fold, P = 0.0364; kidney injury molecule-1: 40 [16, 49] vs.13 [4, 223]-fold, P = 0.0704), lower bacterial loading, and enhanced leukocyte peritoneal recruitment and phagocytic activities at 24 h. Moreover, stool slurry from wild-type and Toll-like receptor 7 knockout mice resulted in similar level of sepsis severity, peritoneal cytokines, and leukocyte recruitment in wild-type animals after peritoneal injection. Conclusions Toll-like receptor 7 plays an important role in the pathogenesis of polymicrobial sepsis by mediating host innate immune responses and contributes to acute kidney injury and mortality.

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Mycobacterium tuberculosisinhibits human innate immune responses via the production of TLR2 antagonist glycolipids

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1707840114 ◽

2017 ◽

Vol 114 (42) ◽

pp. 11205-11210 ◽

Cited By ~ 33

Author(s):

Landry Blanc ◽

Martine Gilleron ◽

Jacques Prandi ◽

Ok-ryul Song ◽

Mi-Seon Jang ◽

...

Keyword(s):

Immune Responses ◽

Molecular Mechanisms ◽

Cytokine Production ◽

Cell Envelope ◽

Costimulatory Molecule ◽

Immune Defense ◽

Innate Immune ◽

Host Cells ◽

Innate Immune Responses ◽

Reporter System

Mycobacterium tuberculosisis a major human pathogen that is able to survive inside host cells and resist immune clearance. Most particularly, it inhibits several arms of the innate immune response, including phagosome maturation or cytokine production. To better understand the molecular mechanisms by whichM. tuberculosiscircumvents host immune defenses, we used a transposon mutant library generated in a virulent clinical isolate ofM. tuberculosisof the W/Beijing family to infect human macrophages, utilizing a cell line derivative of THP-1 cells expressing a reporter system for activation of the transcription factor NF-κB, a key regulator of innate immunity. We identified severalM. tuberculosismutants inducing a NF-κB activation stronger than that of the wild-type strain. One of these mutants was found to be deficient for the synthesis of cell envelope glycolipids, namely sulfoglycolipids, suggesting that the latter can interfere with innate immune responses. Using natural and synthetic molecular variants, we determined that sulfoglycolipids inhibit NF-κB activation and subsequent cytokine production or costimulatory molecule expression by acting as competitive antagonists of Toll-like receptor 2, thereby inhibiting the recognition ofM. tuberculosisby this receptor. Our study reveals that producing glycolipid antagonists of pattern recognition receptors is a strategy used byM. tuberculosisto undermine innate immune defense. Sulfoglycolipids are major and specific lipids ofM. tuberculosis, considered for decades as virulence factors of the bacilli. Our study uncovers a mechanism by which they may contribute toM. tuberculosisvirulence.

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