Poxviral protein E3–altered cytokine production reveals that DExD/H-box helicase 9 controls Toll-like receptor–stimulated immune responses

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.

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

Infection and Immunity ◽

10.1128/iai.01961-14 ◽

2014 ◽

Vol 82 (7) ◽

pp. 3076-3086 ◽

Cited By ~ 38

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.

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Precision N-Glycoproteomic Profiling of Murine Peritoneal Macrophages After Different Stimulations

Frontiers in Immunology ◽

10.3389/fimmu.2021.722293 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lujie Yang ◽

Tianqi Gong ◽

Huali Shen ◽

Jiangnan Pei ◽

Lei Zhang ◽

...

Keyword(s):

Immune Responses ◽

Macrophage Activation ◽

Cytokine Production ◽

Peritoneal Macrophages ◽

Biological Processes ◽

Toll Like Receptor ◽

Adaptive Immune ◽

Murine Peritoneal Macrophages ◽

Molecular Patterns ◽

Stimulation Of

Macrophages are important immune cells that participate in both innate and adaptive immune responses, such as phagocytosis, recognition of molecular patterns, and activation of the immune response. In this study, murine peritoneal macrophages were isolated and then activated by LPS, HSV and VSV. Integrative proteomic and precision N-glycoproteomic profiling were conducted to assess the underlying macrophage activation. We identified a total of 587 glycoproteins, including 1239 glycopeptides, 526 monosaccharide components, and 8326 intact glycopeptides in glycoproteomics, as well as a total of 4496 proteins identified in proteomic analysis. These glycoproteins are widely involved in important biological processes, such as antigen presentation, cytokine production and glycosylation progression. Under the stimulation of the different pathogens, glycoproteins showed a dramatic change. We found that receptors in the Toll-like receptor pathway, such as Tlr2 and CD14, were increased under LPS and HSV stimulation. Glycosylation of those proteins was proven to influence their subcellular locations.

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DNA Sensing in the Innate Immune Response

Physiology ◽

10.1152/physiol.00022.2019 ◽

2020 ◽

Vol 35 (2) ◽

pp. 112-124 ◽

Cited By ~ 3

Author(s):

Benoit Briard ◽

David E. Place ◽

Thirumala-Devi Kanneganti

Keyword(s):

Immune Responses ◽

Cytokine Production ◽

Rna Polymerase Iii ◽

Innate Immune ◽

Toll Like Receptor ◽

Dna Sensing ◽

Dead Box ◽

A Cell ◽

Cell Cytosol ◽

Molecular Patterns

The innate immune system recognizes conserved pathogen-associated molecular patterns and produces inflammatory cytokines that direct downstream immune responses. The inappropriate localization of DNA within the cell cytosol or endosomal compartments indicates that a cell may either be infected by a DNA virus or bacterium, or has problems with its own nuclear integrity. This DNA is sensed by certain receptors that mediate cytokine production and, in some cases, initiate an inflammatory and lytic form of cell death called pyroptosis. Dysregulation of these DNA-sensing pathways is thought to contribute to autoimmune diseases and the development of cancer. In this review, we will discuss the DNA sensors Toll-like receptor 9 (TLR9), cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), absent in melanoma 2 (AIM2), and interferon gamma-inducible 16 (IFI16), their ligands, and their physiological significance. We will also examine the less-well-understood DEAH- and DEAD-box helicases DHX9, DHX36, DDX41, and RNA polymerase III, each of which may play an important role in DNA-mediated innate immunity.

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CpG Oligodeoxynucleotide Developed For Activating Primate Immune Responses Promotes Anti-Tumoral Effect Combine With Neo-Antigen Based mRNA Cancer Vaccine

10.21203/rs.3.rs-148613/v1 ◽

2021 ◽

Author(s):

Rongkuan Hu ◽

Qin Li ◽

Jie Ren ◽

Wei Liu ◽

Guoqin Jiang

Keyword(s):

Immune Responses ◽

Cancer Vaccine ◽

Cancer Vaccines ◽

Cytokine Production ◽

Toll Like Receptor ◽

Human Pbmc ◽

Cpg Oligodeoxynucleotides ◽

Adaptive Immune ◽

Cpg Oligodeoxynucleotide

Abstract Synthetic phosphorthiolate modified CPG-oligodeoxynucleotides (CPG-ODN) activate innate and adaptive immune responses, which being exploited as a therapeutic approach. Here, we first screened and identified a new CpG-B class ODN (CpG2018B) that effectively stimulates type II interferon both in mouse Plasmacytoid dendritic cells (p-DC) and human PBMC. In addition, CpG2018B promotes cytokine production mainly via toll-like receptor 9 (TLR9) pathways. We further demonstrated that intratumoral (IT) injection of CpG2018B inhibits melanoma growth in syngeneic models and could turn “cold” tumors into “hot” tumors. Then, CpG2018B and mRNA based neo-antigen cancer vaccine were encapsulated into lipid-nanoparticle (LNP) and intratumoral injected into melanoma mice models. Interestingly, vaccination with CpG or mRNA vaccine alone could inhibit tumor growth respectively, while, CpG combine with mRNA vaccine enhanced the anti-tumor effect. At last, we described the long-term safety and tolerability of CpG2018B and mRNA therapy in mice models. In conclusion, we identified a novel CpG-B ODNs to promote immune response and CpG combine with mRNA cancer vaccines are attractive candidate for immune stimulatory sequences (ISS) based therapeutic strategies.

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