scholarly journals Regulation of MyD88-Dependent Signaling Events by S Nitrosylation Retards Toll-Like Receptor Signal Transduction and Initiation of Acute-Phase Immune Responses

2007 ◽  
Vol 28 (4) ◽  
pp. 1338-1347 ◽  
Author(s):  
Takeshi Into ◽  
Megumi Inomata ◽  
Misako Nakashima ◽  
Ken-ichiro Shibata ◽  
Hans Häcker ◽  
...  
Keyword(s):  
Immune Responses ◽  
Acute Phase ◽  
Inflammatory Responses ◽  
Adaptor Protein ◽  
Suppressive Effect ◽  
Cysteine Residue ◽  
Oxidative Modification ◽  
Slight Reduction ◽  
Toll Like Receptor ◽  
Signaling Events

ABSTRACT Nitric oxide (NO) has been thought to regulate the immune system through S nitrosylation of the transcriptional factor NF-κB. However, regulatory effects of NO on innate immune responses are unclear. Here, we report that NO has a capability to control Toll-like receptor-mediated signaling through S nitrosylation. We found that the adaptor protein MyD88 was primarily S nitrosylated, depending on the presence of endothelial NO synthase (eNOS). S nitrosylation at a particular cysteine residue within the TIR domain of MyD88 resulted in slight reduction of the NF-κB-activating property. This modification could be restored by the antioxidant glutathione. Through S nitrosylation, NO could negatively regulate the multiple steps of MyD88 functioning, including translocation to the cell membrane after LPS stimulation, interaction with TIRAP, binding to TRAF6, and induction of IκBα phosphorylation. Interestingly, glutathione could reversely neutralize such NO-derived effects. We also found that an acute febrile response to LPS was precipitated in eNOS-deficient mice, indicating that eNOS-derived NO exerts an initial suppressive effect on inflammatory processes. Thus, NO has a potential to retard induction of MyD88-dependent signaling events through the reversible and oxidative modification by NO, by which precipitous signaling reactions are relieved. Such an effect may reflect appropriate regulation of the acute-phase inflammatory responses in living organisms.

scholarly journals Talin1 controls dendritic cell activation by regulating TLR complex assembly and signaling

2020 ◽  
Vol 217 (8) ◽  
Author(s):  
Thomas Jun Feng Lim ◽  
Maegan Bunjamin ◽  
Christiane Ruedl ◽  
I-hsin Su
Keyword(s):  
Immune Responses ◽  
Cell Activation ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Tolerance Induction ◽  
Direct Interaction ◽  
Toll Like Receptor ◽  
Dendritic Cell Activation ◽  
Dependent Cell ◽  
Draining Lymph Nodes

Talin critically controls integrin-dependent cell migration, but its regulatory role in skin dendritic cells (DCs) during inflammatory responses has not been investigated. Here, we show that talin1 regulates not only integrin-dependent Langerhans cell (LC) migration, but also MyD88-dependent Toll-like receptor (TLR)–stimulated DC activation. Talin1-deficient LCs failed to exit the epidermis, resulting in reduced LC migration to skin-draining lymph nodes (sdLNs) and defective skin tolerance induction, while talin1-deficient dermal DCs unexpectedly accumulated in the dermis despite their actomyosin-dependent migratory capabilities. Furthermore, talin1-deficient DCs exhibited compromised chemotaxis, NFκB activation, and proinflammatory cytokine production. Mechanistically, talin1 was required for the formation of preassembled TLR complexes in DCs at steady state via direct interaction with MyD88 and PIP5K. Local production of PIP2 by PIP5K then recruited TIRAP to the preassembled complexes, which were required for TLR signalosome assembly during DC activation. Thus, talin1 regulates MyD88-dependent TLR signaling pathways in DCs through a novel mechanism with implications for antimicrobial and inflammatory immune responses.

scholarly journals Toll-Like Receptor 9 Modulates Immune Responses to Aspergillus fumigatus Conidia in Immunodeficient and Allergic Mice

2008 ◽  
Vol 77 (1) ◽  
pp. 108-119 ◽  
Author(s):  
Hemanth Ramaprakash ◽  
Toshihiro Ito ◽  
Theodore J. Standiford ◽  
Steven L. Kunkel ◽  
Cory M. Hogaboam
Keyword(s):  
Immune Responses ◽  
Aspergillus Fumigatus ◽  
Inflammatory Responses ◽  
Fungal Growth ◽  
Lower Airway ◽  
Interleukin 17 ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Immunodeficient Mice

ABSTRACT The role of Toll-like receptor 9 (TLR9) in antifungal responses in the immunodeficient and allergic host is unclear. We investigated the role of TLR9 in murine models of invasive aspergillosis and fungal asthma. Neutrophil-depleted TLR9 wild-type (TLR9+/+) and TLR9-deficient (TLR9−/−) mice were challenged with resting or swollen Aspergillus fumigatus conidia and monitored for survival and lung inflammatory responses. The absence of TLR9 delayed, but did not prevent, mortality in immunodeficient mice challenged with resting or swollen conidia compared to TLR9+/+ mice. In a fungal asthma model, TLR9+/+ and TLR9−/− mice were sensitized to soluble A. fumigatus antigens and challenged with resting or swollen A. fumigatus conidia, and both groups of mice were analyzed prior to and at days 7, 14, and 28 after the conidium challenge. When challenged with resting conidia, TLR9−/− mice exhibited significantly lower airway hyper-responsiveness compared to the TLR9+/+ groups. In contrast, A. fumigatus-sensitized TLR9−/− mice exhibited pulmonary fungal growth at days 14 and 28 after challenge with swollen conidia, a finding never observed in their allergic wild-type counterparts. Increased fungal growth in allergic TLR9−/− mice correlated with markedly decreased dectin-1 expression in whole lung samples and isolated dendritic cell populations. Further, whole lung levels of interleukin-17 were lower in allergic TLR9−/− mice compared to similar TLR9+/+ mice. Together, these data suggest that TLR9 modulates pulmonary antifungal immune responses to swollen conidia, possibly through the regulation of dectin-1 expression.

Functional Characterization of Signaling Events Underlying Immunostimulatory and Immunosuppressive Activity of Macrophages.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1273-1273
Author(s):  
Mercedes Kloss ◽  
Lothar Kanz ◽  
Helmut R Salih ◽  
Matthias Krusch
Keyword(s):  
Immune Responses ◽  
Molecular Mechanisms ◽  
Functional Characterization ◽  
Gene Array ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Gm Csf ◽  
Differential Expression Pattern ◽  
Signaling Events ◽  
Anti Inflammatory

Abstract Macrophages (Mo) play an important role in combating infectious pathogens and regulating adaptive immune responses. Their reactivity is, among others, guided by pattern recognition receptors including Toll like receptor 4 (TLR4), which recognizes bacterial lipopolysaccharide (LPS). After stimulation, TLR4 can associate with different adaptor proteins like e.g. MyD88 or TRIF leading to the activation of signaling molecules like MAPK or NF-κB. However, stimulation with LPS may result in equally impressive immunostimulatory and immunosuppressive Mo responses. The signaling events responsible for this diametrical behavior of different Mo subsets are yet not fully understood. To study the effects of LPS on Mo we differentiated monocytes of healthy donors with GM-CSF and M-CSF into pro-inflammatory type 1 (Mo1) or anti-inflammatory type 2 (Mo2) subsets, respectively. As expected, upon LPS stimulation the pro-inflammatory Mo1 secreted low levels of the immunosuppressive cytokine IL-10 and high levels of IL-12, while the anti-inflammatory Mo2 produced neglectable amounts of IL-12 but high levels of IL-10. To elucidate the underlying molecular mechanisms we performed gene array analyses with Mo1 compared to Mo2 from three independent donors. Interestingly, among over 50 genes involved in TLR4 signaling, only TLR4 itself and its adaptor protein MyD88 were found to be differentially regulated: Within the immunosuppressive Mo2 subset, MyD88 was significantly downregulated, while a significant upregulation of TLR4 was observed compared to the immunostimulatory Mo1 subset. The differential expression pattern were further confirmed on protein level by western blot. Since TLR4 stimulation leads to MyD88-dependent activation of the MAPK JNK, we investigated whether JNK was differentially involved in cytokine production of Mo1 and Mo2. Addition of a specific JNK inhibitor (SB600125) concentration dependently reduced TLR4-induced IL-10 but enhanced IL-12 production in Mo1, pointing to an immunoinhibitory role of JNK in Mo1. In contrast, inhibition of JNK did not alter the secreted levels of IL-12 or IL-10 in Mo2, indicating that rather MyD88-independent pathways are responsible for the anti-inflammatory behavior of Mo2. In conclusion, our data suggest that the opposite regulation of the adaptor molecule MyD88 in pro- and anti-inflammatory Mo subsets is responsible for the fact that a single, non-polymorphic receptor like TLR4 can mediate both pro- and anti-inflammatory immune responses in Mo.

scholarly journals Impaired Toll-Like Receptor 3-Mediated Immune Responses from Macrophages of Patients Chronically Infected with Hepatitis C Virus

2012 ◽  
Vol 20 (2) ◽  
pp. 146-155 ◽  
Author(s):  
Feng Qian ◽  
Christopher R. Bolen ◽  
Chunxia Jing ◽  
Xiaomei Wang ◽  
Wei Zheng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Immune Responses ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
The United States ◽  
Toll Like Receptor

ABSTRACTHepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States, with the majority of patients becoming chronically infected and a subset (20%) progressing to cirrhosis and hepatocellular carcinoma. Individual variations in immune responses may help define successful resistance to infection with HCV. We have compared the immune response in primary macrophages from patients who have spontaneously cleared HCV (viral load negative [VL−],n= 37) to that of primary macrophages from HCV genotype 1 chronically infected (VL+) subjects (n= 32) and found that macrophages from VL− subjects have an elevated baseline expression of Toll-like receptor 3 (TLR3). Macrophages from HCV patients were stimulatedex vivothrough the TLR3 pathway and assessed using gene expression arrays and pathway analysis. We found elevated TLR3 response genes and pathway activity from VL− subjects. Furthermore, macrophages from VL− subjects showed higher production of beta interferon (IFN-β) and related IFN response genes by quantitative PCR (Q-PCR) and increased phosphorylation of STAT-1 by immunoblotting. Analysis of polymorphisms in TLR3 revealed a significant association of intronic TLR3 polymorphism (rs13126816) with the clearance of HCV and the expression of TLR3. Of note, peripheral blood mononuclear cells (PBMCs) from the same donors showed opposite changes in gene expression, suggesting ongoing inflammatory responses in PBMCs from VL+ HCV patients. Our results suggest that an elevated innate immune response enhances HCV clearance mechanisms and may offer a potential therapeutic approach to increase viral clearance.

scholarly journals Dietary Silk Peptide Inhibits LPS-Induced Inflammatory Responses by Modulating Toll-Like Receptor 4 (TLR4) Signaling

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 771
Author(s):  
Sungwoo Chei ◽  
Hyun-Ji Oh ◽  
Kippeum Lee ◽  
Heegu Jin ◽  
Jeong-Yong Lee ◽  
...  
Keyword(s):  
Immune Responses ◽  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Serum Samples ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
Tlr4 Signaling Pathway ◽  
Silk Peptide

Acid-hydrolyzed silk peptide (SP) is a valuable material that has been used traditionally to treat various diseases, however, the mechanism by which it affects inflammatory responses is unknown. To examine the effects of SP on inflammatory responses, we used macrophages as a vehicle for examining signaling via toll-like receptor 4 (TLR4), which plays an important role in innate immune responses to pathogenic infections and pathogen-derived molecules such as lipopolysaccharide (LPS). We then confirmed the anti-inflammatory effects of SP by examining lymph node, spleen, and serum samples from C57BL/6 mice injected with LPS. We also used LPS-induced bone marrow-derived macrophages and RAW264.7 cells (a murine macrophage cell line) to identify the mechanism by which SP modulates immune responses via the TLR4 signaling pathway. In addition, we showed that SP prevents LPS-induced production of nitric oxide and reactive oxygen species. In summary, SP inhibits LPS-induced inflammatory responses by modulating the TLR4 signaling pathway.

scholarly journals Cytadherence of Mycoplasma pneumoniae Induces Inflammatory Responses through Autophagy and Toll-Like Receptor 4

2014 ◽  
Vol 82 (7) ◽  
pp. 3076-3086 ◽  
Author(s):  
Takashi Shimizu ◽  
Yui Kimura ◽  
Yutaka Kida ◽  
Koichi Kuwano ◽  
Masato Tachibana ◽  
...  
Keyword(s):  
Immune Responses ◽  
Mycoplasma Pneumoniae ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Hypothetical Protein ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Content Type ◽  
Toll Like Receptor 2

ABSTRACTMycoplasma pneumoniaecauses pneumonia, tracheobronchitis, pharyngitis, and asthma in humans. The pathogenesis ofM. pneumoniaeinfection is attributed to excessive immune responses. We previously demonstrated thatM. pneumoniaelipoproteins induced inflammatory responses through Toll-like receptor 2 (TLR2). In the present study, we demonstrated thatM. pneumoniaeinduced strong inflammatory responses in macrophages derived from TLR2 knockout (KO) mice. Cytokine production in TLR2 KO macrophages was increased compared with that in the macrophages of wild-type (WT) mice. Heat-killed, antibiotic-treated, and overgrownM. pneumoniaefailed to induce inflammatory responses in TLR2 KO macrophages. 3-Methyladenine and chloroquine, inhibitors of autophagy, decreased the induction of inflammatory responses in TLR2 KO macrophages. These inflammatory responses were also inhibited in macrophages treated with the TLR4 inhibitor VIPER and those obtained from TLR2 and TLR4 (TLR2/4) double-KO mice. Two mutants that lacked the ability to induce inflammatory responses in TLR2 KO macrophages were obtained by transposon mutagenesis. The transposons were inserted inatpCencoding an ATP synthase F0F1 ε subunit andF10_orf750encoding hypothetical protein MPN333. These mutants showed deficiencies in cytadherence. These results suggest that cytadherence ofM. pneumoniaeinduces inflammatory responses through TLR4 and autophagy.

scholarly journals HIP-55 Is Important for T-Cell Proliferation, Cytokine Production, and Immune Responses

2005 ◽  
Vol 25 (16) ◽  
pp. 6869-6878 ◽  
Author(s):  
Jin Han ◽  
Jr-Wen Shui ◽  
Xuejun Zhang ◽  
Biao Zheng ◽  
Shuhua Han ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Knockout Mice ◽  
Cytokine Production ◽  
Adaptor Protein ◽  
T Cell Proliferation ◽  
Tcr Signaling ◽  
Signaling Events

ABSTRACT Engagement of the T-cell receptor (TCR) triggers a series of signaling events that lead to the activation of T cells. HIP-55 (SH3P7 or mAbp1), an actin-binding adaptor protein, interacts with and is tyrosine phosphorylated by ZAP-70, which is a crucial proximal protein tyrosine kinase for TCR signaling. HIP-55 is important for JNK and HPK1 activation induced by TCR signaling. In this study, we report the generation and characterization of HIP-55 knockout mice. We found that HIP-55 knockout mice were viable and fertile but showed decreased body weight and increased occurrence of death within the first 4 weeks after birth. The lymphoid organs in HIP-55 knockout mice showed cellularity and T-cell development comparable to that of the wild-type mice. HIP-55 knockout T cells displayed defective T-cell proliferation, decreased cytokine production, and decreased up-regulation of the activation markers induced by TCR stimulation. TCR internalization was slightly increased in HIP-55 knockout T cells. These phenotypes were accompanied by reduced immune responses, including antigen-specific antibody production and T-cell proliferation in HIP-55 knockout mice. The TCR-induced signaling events, including LAT/phospholipase Cγ1 phosphorylation and HPK1/JNK activation, were partially defective in HIP-55 knockout T cells. These results demonstrate the importance of HIP-55 as an adaptor protein in the TCR signaling and immune system.

scholarly journals Immunopathogenesis of Craniotomy Infection and Niche-Specific Immune Responses to Biofilm

2021 ◽  
Vol 12 ◽  
Author(s):  
Sharon DB de Morais ◽  
Gunjan Kak ◽  
Joseph P. Menousek ◽  
Tammy Kielian
Keyword(s):  
Immune Responses ◽  
Bacterial Infections ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Critical Role ◽  
Adaptor Protein ◽  
Anatomical Location ◽  
Life Threatening ◽  
The Central Nervous System ◽  
Biofilm Infection

Bacterial infections in the central nervous system (CNS) can be life threatening and often impair neurological function. Biofilm infection is a complication following craniotomy, a neurosurgical procedure that involves the removal and replacement of a skull fragment (bone flap) to access the brain for surgical intervention. The incidence of infection following craniotomy ranges from 1% to 3% with approximately half caused by Staphylococcus aureus (S. aureus). These infections present a significant therapeutic challenge due to the antibiotic tolerance of biofilm and unique immune properties of the CNS. Previous studies have revealed a critical role for innate immune responses during S. aureus craniotomy infection. Experiments using knockout mouse models have highlighted the importance of the pattern recognition receptor Toll-like receptor 2 (TLR2) and its adaptor protein MyD88 for preventing S. aureus outgrowth during craniotomy biofilm infection. However, neither molecule affected bacterial burden in a mouse model of S. aureus brain abscess highlighting the distinctions between immune regulation of biofilm vs. planktonic infection in the CNS. Furthermore, the immune responses elicited during S. aureus craniotomy infection are distinct from biofilm infection in the periphery, emphasizing the critical role for niche-specific factors in dictating S. aureus biofilm-leukocyte crosstalk. In this review, we discuss the current knowledge concerning innate immunity to S. aureus craniotomy biofilm infection, compare this to S. aureus biofilm infection in the periphery, and discuss the importance of anatomical location in dictating how biofilm influences inflammatory responses and its impact on bacterial clearance.

scholarly journals Macrophage activation on “phagocytic synapse” arrays: Spacing of nanoclustered ligands directs TLR1/2 signaling with an intrinsic limit

2020 ◽  
Vol 6 (49) ◽  
pp. eabc8482
Author(s):  
Miao Li ◽  
Haomin Wang ◽  
Wenqian Li ◽  
Xiaoji G. Xu ◽  
Yan Yu
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Quantitative Relationship ◽  
Toll Like Receptor ◽  
Spatial Cues ◽  
Cell Level ◽  
Host Immune Responses ◽  
Cell Responses ◽  
Receptor Clusters

The activation of Toll-like receptor heterodimer 1/2 (TLR1/2) by microbial components plays a critical role in host immune responses against pathogens. TLR1/2 signaling is sensitive to the chemical structure of ligands, but its dependence on the spatial distribution of ligands on microbial surfaces remains unexplored. Here, we reveal the quantitative relationship between TLR1/2-triggered immune responses and the spacing of ligand clusters by designing an artificial “phagocytic synapse” nanoarray platform to mimic the cell-microbe interface. The ligand spacing dictates the proximity of receptor clusters on the cell surface and consequently the pro-inflammatory responses of macrophages. However, cell responses reach their maximum at small ligand spacings when the receptor nanoclusters become adjacent to one another. Our study demonstrates the feasibility of using spatially patterned ligands to modulate innate immunity. It shows that the receptor clusters of TLR1/2 act as a driver in integrating the spatial cues of ligands into cell-level activation events.

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