scholarly journals Plexin-A4–semaphorin 3A signaling is required for Toll-like receptor– and sepsis-induced cytokine storm

2010 ◽  
Vol 207 (13) ◽  
pp. 2943-2957 ◽  
Author(s):  
Haitao Wen ◽  
Yu Lei ◽  
So-Young Eun ◽  
Jenny P.-Y. Ting
Keyword(s):  
Cecal Ligation ◽  
Innate Immune ◽  
Cytokine Storm ◽  
Semaphorin 3A ◽  
Tlr Signaling ◽  
Inflammatory Cytokine Production ◽  
Autocrine Loop ◽  
Tlr Agonists ◽  
Tlr Agonist

Plexins and semaphorins are ligand–receptor pairs that serve as guidance molecules in the nervous system and play some roles in immunity. Plexins are similar to the Toll-like receptors (TLRs) in their evolutionary conservation from flies to mammals. By studying plexin-A4–deficient (Plxna4−/−) innate immune cells, in this study we show a novel influence of plexin-A4 on TLR signaling. Plxna4−/− cells exhibit defective inflammatory cytokine production upon activation by a spectrum of TLR agonists and bacteria. Plexin-A4 is required for TLR-induced activation of the small guanosine triphosphate hydrolase (GTPase) Rac1 (ras-related C3 botulinum toxin substrate 1). Rac1 activation is accompanied by JNK (c-Jun N-terminal kinase) and NF-κB activation, culminating in TLR-induced binding of NF-κB and AP-1 to the promoters of inflammatory cytokines. Plxna4−/− mice are remarkably resistant to TLR agonist–induced inflammation and polymicrobial peritonitis caused by cecal ligation and puncture. Administration of a ligand of plexin-A4, Sema3A (semaphorin 3A), exacerbates the cytokine storm caused by TLR agonists and bacterial sepsis. TLR engagement can induce Sema3A expression, thus completing an autocrine loop. These findings expand the role of plexins to TLR signaling and suggest plexin-A4 and Sema3A as new intervention points for treating sepsis.

scholarly journals The Role of JAK-3 in Regulating TLR-Mediated Inflammatory Cytokine Production in Innate Immune Cells

2013 ◽  
Vol 191 (3) ◽  
pp. 1164-1174 ◽  
Author(s):  
Huizhi Wang ◽  
Jonathan Brown ◽  
Shegan Gao ◽  
Shuang Liang ◽  
Ravi Jotwani ◽  
...  
Keyword(s):  
Immune Cells ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Inflammatory Cytokine Production

scholarly journals Innate immune responses after stimulation with Toll-like receptor agonists in ex vivo microglial cultures and an in vivo model using mice with reduced microglia

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
James A. Carroll ◽  
Brent Race ◽  
Katie Williams ◽  
James F. Striebel ◽  
Bruce Chesebro
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Ex Vivo ◽  
Innate Immune ◽  
Cpg Odn ◽  
Innate Immune Responses ◽  
Tlr Signaling ◽  
Tlr Agonists ◽  
Tlr7 Agonist

Abstract Background Past experiments studying innate immunity in the central nervous system (CNS) utilized microglia obtained from neonatal mouse brain, which differ developmentally from adult microglia. These differences might impact our current understanding of the role of microglia in CNS development, function, and disease. Methods Cytokine protein secretion was compared in ex vivo P3 and adult microglial cultures after exposure to agonists for three different toll-like receptors (TLR4, lipopolysaccharide [LPS]; TLR7, imiquimod [IMQ]; and TLR9, CpG Oligodeoxynucleotide [CpG-ODN] 1585). In addition, changes in inflammatory gene expression in ex vivo adult microglia in response to the TLR agonists was assessed. Furthermore, in vivo experiments evaluated changes in gene expression associated with inflammation and TLR signaling in brains of mice with or without treatment with PLX5622 to reduce microglia. Results Ex vivo adult and P3 microglia increased cytokine secretion when exposed to TLR4 agonist LPS and to TLR7 agonist IMQ. However, adult microglia decreased expression of numerous genes after exposure to TLR 9 agonist CpG-ODN 1585. In contrast, in vivo studies indicated a core group of inflammatory and TLR signaling genes increased when each of the TLR agonists was introduced into the CNS. Reducing microglia in the brain led to decreased expression of various inflammatory and TLR signaling genes. Mice with reduced microglia showed extreme impairment in upregulation of genes after exposure to TLR7 agonist IMQ. Conclusions Cultured adult microglia were more reactive than P3 microglia to LPS or IMQ exposure. In vivo results indicated microglial influences on neuroinflammation were agonist specific, with responses to TLR7 agonist IMQ more dysregulated in mice with reduced microglia. Thus, TLR7-mediated innate immune responses in the CNS appeared more dependent on the presence of microglia. Furthermore, partial responses to TLR4 and TLR9 agonists in mice with reduced microglia suggested other cell types in the CNS can compensate for their absence.

Impaired Toll-like receptor 8–mediated IL-6 and TNF-α production in antigen-presenting cells from patients with X-linked agammaglobulinemia

Blood ◽  
2006 ◽  
Vol 109 (6) ◽  
pp. 2553-2556 ◽  
Author(s):  
Klára Sochorová ◽  
Rudolf Horváth ◽  
Daniela Rožková ◽  
Jiří Litzman ◽  
Jiřina Bartůňková ◽  
...  
Keyword(s):  
Critical Role ◽  
Toll Like Receptor ◽  
Normal Numbers ◽  
Tlr Signaling ◽  
Tlr Agonists ◽  
Tnf Α ◽  
Bruton Tyrosine Kinase ◽  
Antigen Presenting ◽  
Stimulation Of

Abstract The critical role of Bruton tyrosine kinase (Btk) in B cells has been documented by the block of B-cell development in X-linked agammaglobulinemia (XLA). Less is known about Btk function in myeloid cells. Several pieces of evidence indicate that Btk is a component of Toll-like receptor (TLR) signaling. We analyzed whether Btk deficiency in XLA is associated with an impaired dendritic cell (DC) compartment or defective TLR signaling. We analyzed the expression of TLRs 1 to 9 on myeloid DCs generated from XLA patients and evaluated their response to activation by specific TLR agonists. We show that XLA patients have normal numbers of circulating DCs. Btk-deficient DCs have no defect in response to stimulation of TLRs 1/2, 2/6, 3, 4, and 5 but display a profound impairment of IL-6 and TNF-α production in response to stimulation by TLR-8 cognate agonist, ssRNA. These findings may provide an explanation for the susceptibility to enteroviral infections in XLA patients.

scholarly journals Differential Depletion of Bone Marrow Resident B-ALL after Systemic Administration of Endosomal TLR Agonists

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 169
Author(s):  
Sumin Jo ◽  
Abbas Fotovati ◽  
Jesus Duque-Afonso ◽  
Michael L. Cleary ◽  
Peter van den Elzen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Systemic Administration ◽  
Innate Immune ◽  
Immune Activity ◽  
Tlr Agonists ◽  
Tlr Agonist ◽  
Organ Specific

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. While frontline chemotherapy regimens are generally very effective, the prognosis for patients whose leukemia returns remains poor. The presence of measurable residual disease (MRD) in bone marrow at the completion of induction therapy is the strongest predictor of relapse, suggesting that strategies to eliminate the residual leukemic blasts from this niche could reduce the incidence of recurrence. We have previously reported that toll-like receptor (TLR) agonists achieve durable T cell-mediated protection in transplantable cell line-based models of B cell precursor leukemia (B-ALL). However, the successful application of TLR agonist therapy in an MRD setting would require the induction of anti-leukemic immune activity specifically in the bone marrow, a site of the chemotherapy-resistant leukemic blasts. In this study, we compare the organ-specific depletion of human and mouse primary B-ALL cells after systemic administration of endosomal TLR agonists. Despite comparable splenic responses, only the TLR9 agonist induced strong innate immune responses in the bone marrow and achieved a near-complete elimination of B-ALL cells. This pattern of response was associated with the most significantly prolonged disease-free survival. Overall, our findings identify innate immune activity in the bone marrow that is associated with durable TLR-induced protection against B-ALL outgrowth.

Role of Innate Immune Sensors, TLRs, and NALP3 in Rheumatoid Arthritis and Osteoarthritis

2014 ◽  
Vol 24 (4) ◽  
pp. 243-251 ◽  
Author(s):  
Yuya Takakubo ◽  
G. Barreto ◽  
Yrjo T. Konttinen ◽  
H. Oki ◽  
Michiaki Takagi
Keyword(s):  
Rheumatoid Arthritis ◽  
Innate Immune

scholarly journals NF-κB, JNK, and TLR Signaling Pathways in Hepatocarcinogenesis

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Shin Maeda
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathways ◽  
Inflammatory Cell ◽  
Prognostic Markers ◽  
Tumor Promotion ◽  
Neoplastic Cell ◽  
Nuclear Factor ◽  
Tlr Signaling ◽  
The Third

Hepatocellular carcinoma (HCC) is the third largest cause of cancer deaths worldwide. The role of molecular changes in HCC have been used to identify prognostic markers and chemopreventive or therapeutic targets. It seems that toll-like receptors (TLRs) as well as the nuclear factor (NF)-κB, and JNK pathways are critical regulators for the production of the cytokines associated with tumor promotion. The cross-talk between an inflammatory cell and a neoplastic cell, which is instigated by the activation of NF-κB and JNKs, is critical for tumor organization. JNKs also regulate cell proliferation and act as oncogenes, making them the main tumor-promoting protein kinases. TLRs play roles in cytokine and hepatomitogen expression mainly in myeloid cells and may promote liver tumorigenesis. A better understanding of these signaling pathways in the liver will help us understand the mechanism of hepatocarcinogenesis and provide a new therapeutic target for HCC.

scholarly journals Primary and Memory Response of Human Monocytes to Vaccines: Role of Nanoparticulate Antigens in Inducing Innate Memory

Nanomaterials ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 931
Author(s):  
Mayra M. Ferrari Ferrari Barbosa ◽  
Alex Issamu Kanno ◽  
Leonardo Paiva Farias ◽  
Mariusz Madej ◽  
Gergö Sipos ◽  
...  
Keyword(s):  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Innate Immune ◽  
Soluble Form ◽  
Neisseria Lactamica ◽  
Particulate Form ◽  
Future Challenges ◽  
Monocytes And Macrophages

Innate immune cells such as monocytes and macrophages are activated in response to microbial and other challenges and mount an inflammatory defensive response. Exposed cells develop the so-called innate memory, which allows them to react differently to a subsequent challenge, aiming at better protection. In this study, using human primary monocytes in vitro, we have assessed the memory-inducing capacity of two antigenic molecules of Schistosoma mansoni in soluble form compared to the same molecules coupled to outer membrane vesicles of Neisseria lactamica. The results show that particulate challenges are much more efficient than soluble molecules in inducing innate memory, which is measured as the production of inflammatory and anti-inflammatory cytokines (TNFα, IL-6, IL-10). Controls run with LPS from Klebsiella pneumoniae compared to the whole bacteria show that while LPS alone has strong memory-inducing capacity, the entire bacteria are more efficient. These data suggest that microbial antigens that are unable to induce innate immune activation can nevertheless participate in innate activation and memory when in a particulate form, which is a notion that supports the use of nanoparticulate antigens in vaccination strategies for achieving adjuvant-like effects of innate activation as well as priming for improved reactivity to future challenges.

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