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 Serine Lipids of Porphyromonas gingivalis Are Human and Mouse Toll-Like Receptor 2 Ligands

2013 ◽  
Vol 81 (9) ◽  
pp. 3479-3489 ◽  
Author(s):  
Robert B. Clark ◽  
Jorge L. Cervantes ◽  
Mark W. Maciejewski ◽  
Vahid Farrokhi ◽  
Reza Nemati ◽  
...  
Keyword(s):  
Cell Activation ◽  
Inflammatory Responses ◽  
Periodontal Pathogen ◽  
Toll Like Receptor ◽  
Dendritic Cell Activation ◽  
Content Type ◽  
Hek Cells ◽  
Toll Like Receptor 2

ABSTRACTThe total cellular lipids ofPorphyromas gingivalis, a known periodontal pathogen, were previously shown to promote dendritic cell activation and inhibition of osteoblasts through engagement of Toll-like receptor 2 (TLR2). The purpose of the present investigation was to fractionate all lipids ofP. gingivalisand define which lipid classes account for the TLR2 engagement, based on bothin vitrohuman cell assays andin vivostudies in mice. Specific serine-containing lipids ofP. gingivalis, called lipid 654 and lipid 430, were identified in specific high-performance liquid chromatography fractions as the TLR2-activating lipids. The structures of these lipids were defined using tandem mass spectrometry and nuclear magnetic resonance methods.In vitro, both lipid 654 and lipid 430 activated TLR2-expressing HEK cells, and this activation was inhibited by anti-TLR2 antibody. In contrast, TLR4-expressing HEK cells failed to be activated by either lipid 654 or lipid 430. Wild-type (WT) or TLR2-deficient (TLR2−/−) mice were injected with either lipid 654 or lipid 430, and the effects on serum levels of the chemokine CCL2 were measured 4 h later. Administration of either lipid 654 or lipid 430 to WT mice resulted in a significant increase in serum CCL2 levels; in contrast, the administration of lipid 654 or lipid 430 to TLR2−/−mice resulted in no increase in serum CCL2. These results thus identify a new class of TLR2 ligands that are produced byP. gingivalisthat likely play a significant role in mediating inflammatory responses both at periodontal sites and, potentially, in other tissues where these lipids might accumulate.

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 Isolation of an endotoxin-MD-2 complex that produces Toll-like receptor 4-dependent cell activation at picomolar concentrations

2004 ◽  
Vol 101 (12) ◽  
pp. 4186-4191 ◽  
Author(s):  
T. L. Gioannini ◽  
A. Teghanemt ◽  
D. Zhang ◽  
N. P. Coussens ◽  
W. Dockstader ◽  
...  
Keyword(s):  
Cell Activation ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Dependent Cell

scholarly journals Evaluation of Newcastle disease virus mediated dendritic cell activation and cross‐priming tumor‐specific immune responses ex vivo

2019 ◽  
Vol 146 (2) ◽  
pp. 531-541 ◽  
Author(s):  
Qi Xu ◽  
Udaya S. Rangaswamy ◽  
Weijia Wang ◽  
Scott H. Robbins ◽  
James Harper ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Immune Responses ◽  
Newcastle Disease Virus ◽  
Disease Virus ◽  
Newcastle Disease ◽  
Cell Activation ◽  
Ex Vivo ◽  
Dendritic Cell Activation

scholarly journals Bacteroides fragilis-Derived Lipopolysaccharide Produces Cell Activation and Lethal Toxicity via Toll-Like Receptor 4

2005 ◽  
Vol 73 (9) ◽  
pp. 5620-5627 ◽  
Author(s):  
Giuseppe Mancuso ◽  
Angelina Midiri ◽  
Carmelo Biondo ◽  
Concetta Beninati ◽  
Maria Gambuzza ◽  
...  
Keyword(s):  
Cell Activation ◽  
Cytokine Production ◽  
Biological Activities ◽  
Endotoxic Shock ◽  
Intestinal Flora ◽  
Bacteroides Fragilis ◽  
Peritoneal Macrophages ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
In Cells

ABSTRACT Bacteroides fragilis, which is part of the normal intestinal flora, is a frequent cause of serious disease, especially in diabetic and surgical patients. In these conditions, B. fragilis lipopolysaccharide (LPS) is likely to play a major pathophysiologic role. B. fragilis LPS is structurally different from classical enterobacterial LPS, whose biological activities are mediated by Toll-like receptor 4 (TLR4) activation. The ability of B. fragilis LPS to activate TLR4 and TLR2 was investigated here, since evidence on this issue is scarce and controversial. Each of four different protein-free B. fragilis LPS preparations could induce interleukin-8 responses in cells cotransfected with TLR4/CD14/MD2 but not TLR4/CD14 alone. Two of the preparations also induced cytokine production in cells cotransfected with TLR2/CD14 or in peritoneal macrophages from TLR4 mutant C3H/HeJ mice. Both of these activities, however, were lost after repurification with a modified phenol reextraction procedure. Importantly, all preparations could induce endotoxic shock in TLR2-deficient mice, but not in TLR4 mutant C3H/HeJ mice. Consistent with these findings, anti-TLR4 and anti-CD14, but not anti-TLR2, antibodies could inhibit B. fragilis LPS-induced cytokine production in human monocytes. Collectively, these results indicate that B. fragilis LPS signals via a TLR4/CD14/MD2-dependent pathway, and it is unable to activate TLR2. Moreover, our data document the occurrence of TLR2-activating contaminants even in highly purified B. fragilis LPS preparations. This may explain earlier contradictory findings on the ability of B. fragilis LPS to activate cells in the absence of functional TLR4. These data may be useful to devise strategies to prevent the pathophysiologic changes observed during B. fragilis sepsis and to better understand structure-activity relationships of LPS.

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.

Suppression of Interferon Regulatory Factor 8 Modulates Toll Like Receptor 2 and Toll Like Receptor 7/8 Induced Dendritic Cell Activation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2573-2573
Author(s):  
Daniela Werth ◽  
Anita Bringmann ◽  
Katharina Brauer ◽  
Karin von Schwarzenberg ◽  
Stefanie Held ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Western Blot ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Cell Activation ◽  
Nuclear Translocation ◽  
Interferon Regulatory Factor ◽  
Toll Like Receptor ◽  
Regulatory Factor ◽  
Dendritic Cell Activation

Abstract Interferon regulatory factor 8 (IRF-8) is a member of the IRF family of transcription factors, which are stimulated through interferon mediated pathways. In mice, IRF-8 seems to play an essential role in the development and maturation of dendritic cells (DCs). However, very limited knowledge is available about the potential role of IRF-8 in the human system. To bridge this gap we analyzed function and activation of human monocyte-derived dendritic cells (mDCs) lacking IRF-8 expression. To knockdown IRF-8 protein levels, we electroporated mDCs with different siRNAs against IRF-8. Additionally, we stimulated the electroporated mDCs with the Toll like receptor (TLR) 2 ligand Pam3Cys or the TLR 7/8 ligand R848. IRF-8 knockdown in mDCs was verified constantly by Western Blot analysis using an anti-IRF-8 antibody. We found that IRF-8 knockdown clearly diminished the expression of the human lymphocyte antigen molecules HLA-ABC and HLA-DR in Pam3Cys and R848 stimulated mDCs. To gain functional data, we performed ELISAs to determine cytokine and chemokine secretion. The electroporation of mDCs with IRF-8 specific siRNA resulted in profound inhibition of secretion of the cytokines IL-6, IL-12 and TNF-a as well as the chemokines MIP-1a (CCL3), MCP-1 (CCL2) and RANTES (CCL5). To get additional information on IRF-8 function in human mDCs, the regulation of signal transduction pathways was determined by Western Blot analysis. The suppression of IRF-8 diminished the nuclear translocation of the NF-kB family member’s c-Rel and RelB as well as PU.1 and IRF-3 in activated mDCs. In addition, we showed that the suppression of IRF-8 caused a reduced phosphorylation of ERK and JNK, but had no effect on the expression of STAT3. In summary, the knockdown of IRF-8 reduced the capability of mDCs to develop appropriate phenotype and functions in response to activating stimuli. Our results indicate that these effects are mediated via the ERK, NF-kB and PU.1 signalling pathways. IRF-8 plays an important role in the activation and function of human mDCs.

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