Toll‐like receptor 4 differentially regulates adult hippocampal neurogenesis in an age‐ and sex‐dependent manner

ABSTRACT Teichuronic acid (TUA), a component of the cell walls of the gram-positive organism Micrococcus luteus (formerlyMicrococcus lysodeikticus), induced inflammatory cytokines in C3H/HeN mice but not in lipopolysaccharide (LPS)-resistant C3H/HeJ mice that have a defect in the Toll-like receptor 4 (TLR4) gene, both in vivo and in vitro, similarly to LPS (T. Monodane, Y. Kawabata, S. Yang, S. Hase, and H. Takada, J. Med. Microbiol. 50:4–12, 2001). In this study, we found that purified TUA (p-TUA) induced tumor necrosis factor alpha (TNF-α) in murine monocytic J774.1 cells but not in mutant LR-9 cells expressing membrane CD14 at a lower level than the parent J774.1 cells. The TNF-α-inducing activity of p-TUA in J774.1 cells was completely inhibited by anti-mouse CD14 monoclonal antibody (MAb). p-TUA also induced interleukin-8 (IL-8) in human monocytic THP-1 cells differentiated to macrophage-like cells expressing CD14. Anti-human CD14 MAb, anti-human TLR4 MAb, and synthetic lipid A precursor IVA, an LPS antagonist, almost completely inhibited the IL-8-inducing ability of p-TUA, as well as LPS, in the differentiated THP-1 cells. Reduced p-TUA did not exhibit any activities in J774.1 or THP-1 cells. These findings strongly suggested that M. luteus TUA activates murine and human monocytic cells in a CD14- and TLR4-dependent manner, similar to LPS.

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SalmonellaFimbrial Protein FimH Is Involved in Expression of Proinflammatory Cytokines in a Toll-Like Receptor 4-Dependent Manner

Infection and Immunity ◽

10.1128/iai.00881-18 ◽

2019 ◽

Vol 87 (3) ◽

Cited By ~ 3

Author(s):

Kei-ichi Uchiya ◽

Yurie Kamimura ◽

Ayumi Jusakon ◽

Toshiaki Nikai

Keyword(s):

Proinflammatory Cytokines ◽

Mitogen Activated Protein Kinase ◽

Hek293 Cells ◽

Dependent Manner ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Content Type ◽

Type 1 Fimbriae ◽

Serovar Typhimurium

ABSTRACTType 1 fimbriae are proteinaceous filamentous structures present on bacterial surfaces and are mainly composed of the major fimbrial protein subunit FimA and the adhesive protein FimH, which is located at the tip of the fimbrial shaft. Here, we investigated the involvement of type 1 fimbriae in the expression of proinflammatory cytokines in macrophages infected withSalmonella entericaserovar Typhimurium. The level of interleukin-1β (IL-1β) mRNA was lower in macrophages infected withfimAorfimHmutant strains than in those infected with wild-typeSalmonella. Treatment of macrophages with purified recombinant FimH protein, but not FimA, resulted in the activation of the mitogen-activated protein kinase and nuclear factor κB signaling pathways, leading to the expression of not only IL-1β but also other proinflammatory cytokines, such as IL-6 and tumor necrosis factor alpha. However, FimH carrying an N-terminal region deletion or heat-treated FimH did not show such effects. The expression of FimH-induced IL-1β was inhibited by treatment with the Toll-like receptor 4 (TLR4) inhibitor TAK-242 but not by treatment with polymyxin B, a lipopolysaccharide antagonist. Furthermore, FimH treatment stimulated HEK293 cells expressing TLR4 and MD-2/CD14 but did not stimulate HEK293 cells expressing only TLR4. Collectively, FimH is a pathogen-associated molecular pattern ofS. entericaserovar Typhimurium that is recognized by TLR4 in the presence of MD-2 and CD14 and plays a significant role in the expression of proinflammatory cytokines inSalmonella-infected macrophages.

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The phytosphingosine-CD300b interaction promotes zymosan-induced, nitric oxide–dependent neutrophil recruitment

Science Signaling ◽

10.1126/scisignal.aar5514 ◽

2019 ◽

Vol 12 (564) ◽

pp. eaar5514 ◽

Cited By ~ 4

Author(s):

Mariko Takahashi ◽

Kumi Izawa ◽

Makoto Urai ◽

Yoshinori Yamanishi ◽

Akie Maehara ◽

...

Keyword(s):

Nitric Oxide ◽

Neutrophil Recruitment ◽

No Production ◽

Dependent Manner ◽

Toll Like Receptor ◽

Wild Type ◽

Neutrophil Accumulation ◽

Toll Like Receptor 4 ◽

Potential Ligand ◽

Inflammatory Dendritic Cells

Zymosan is a glucan that is a component of the yeast cell wall. Here, we determined the mechanisms underlying the zymosan-induced accumulation of neutrophils in mice. Loss of the receptor CD300b reduced the number of neutrophils recruited to dorsal air pouches in response to zymosan, but not in response to lipopolysaccharide (LPS), a bacterial membrane component recognized by Toll-like receptor 4 (TLR4). An inhibitor of nitric oxide (NO) synthesis reduced the number of neutrophils in the zymosan-treated air pouches of wild-type mice to an amount comparable to that inCD300b−/−mice. Treatment with clodronate liposomes decreased the number of NO-producing, CD300b+inflammatory dendritic cells (DCs) in wild-type mice, thus decreasing NO production and neutrophil recruitment. Similarly, CD300b deficiency decreased the NO-dependent recruitment of neutrophils to zymosan-treated joint cavities, thus ameliorating subsequent arthritis. We identified phytosphingosine, a lipid component of zymosan, as a potential ligand of CD300b. Phytosphingosine stimulated NO production in inflammatory DCs and promoted neutrophil recruitment in a CD300b-dependent manner. Together, these results suggest that the phytosphingosine-CD300b interaction promotes zymosan-dependent neutrophil accumulation by inducing NO production by inflammatory DCs and that CD300b may contribute to antifungal immunity.

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Thrombomodulin Attenuates Inflammatory Damage Due to Liver Ischemia and Reperfusion Injury in Mice in Toll-Like Receptor 4-Dependent Manner

American Journal of Transplantation ◽

10.1111/ajt.13991 ◽

2016 ◽

Vol 17 (1) ◽

pp. 69-80 ◽

Cited By ~ 28

Author(s):

K. Kadono ◽

Y. Uchida ◽

H. Hirao ◽

T. Miyauchi ◽

T. Watanabe ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia And Reperfusion ◽

Dependent Manner ◽

Liver Ischemia ◽

Toll Like Receptor ◽

Ischemia And Reperfusion Injury ◽

Toll Like Receptor 4 ◽

Inflammatory Damage

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RETRACTED: Identification of an antitumor immune response of polyhistidine through a toll-like receptor 4-dependent manner

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2014.09.078 ◽

2014 ◽

Vol 453 (1) ◽

pp. 148-152 ◽

Cited By ~ 2

Author(s):

Feng Wang ◽

Yong Yang

Keyword(s):

Immune Response ◽

Antitumor Immune Response ◽

Dependent Manner ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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Toll-Like Receptor 4 Agonistic Antibody Promotes Host Defense against Chronic Pseudomonas aeruginosa Lung Infection in Mice

Infection and Immunity ◽

10.1128/iai.01384-15 ◽

2016 ◽

Vol 84 (7) ◽

pp. 1986-1993 ◽

Cited By ~ 8

Author(s):

Shigeki Nakamura ◽

Naoki Iwanaga ◽

Masafumi Seki ◽

Kenji Fukudome ◽

Kazuhiro Oshima ◽

...

Keyword(s):

Immune Response ◽

Pseudomonas Aeruginosa ◽

Neutrophil Recruitment ◽

Dependent Manner ◽

Bacterial Clearance ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Content Type ◽

Opsonophagocytic Killing

Chronic lower respiratory tract infection withPseudomonas aeruginosais difficult to treat due to enhanced antibiotic resistance and decreased efficacy of drug delivery to destroyed lung tissue. To determine the potential for restorative immunomodulation therapies, we evaluated the effect of Toll-like receptor 4 (TLR4) stimulation on the host immune response toPseudomonasinfection in mice. We implanted sterile plastic tubes precoated withP. aeruginosain the bronchi of mice, administered the TLR4/MD2 agonistic monoclonal antibody UT12 intraperitoneally every week, and subsequently analyzed the numbers of viable bacteria and inflammatory cells and the levels of cytokines. We also performed flow cytometry-based phagocytosis and opsonophagocytic killing assaysin vitrousing UT12-treated murine peritoneal neutrophils. UT12-treated mice showed significantly enhanced bacterial clearance, increased numbers of Ly6G+neutrophils, and increased concentrations of macrophage inflammatory protein 2 (MIP-2) in the lungs (P< 0.05). Depletion of CD4+T cells eliminated the ability of the UT12 treatment to improve bacterial clearance and promote neutrophil recruitment and MIP-2 production. Additionally, UT12-pretreated peritoneal neutrophils exhibited increased opsonophagocytic killing activity via activation of the serine protease pathway, specifically neutrophil elastase activity, in a TLR4-dependent manner. These data indicated that UT12 administration significantly augmented the innate immune response against chronic bacterial infection, in part by promoting neutrophil recruitment and bactericidal function.

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Respiratory Syncytial Virus Fusion Protein-Induced Toll-Like Receptor 4 (TLR4) Signaling Is Inhibited by the TLR4 Antagonists Rhodobacter sphaeroides Lipopolysaccharide and Eritoran (E5564) and Requires Direct Interaction with MD-2

mBio ◽

10.1128/mbio.00218-12 ◽

2012 ◽

Vol 3 (4) ◽

Cited By ~ 64

Author(s):

Prasad Rallabhandi ◽

Rachel L. Phillips ◽

Marina S. Boukhvalova ◽

Lioubov M. Pletneva ◽

Kari Ann Shirey ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Rhodobacter Sphaeroides ◽

Dependent Manner ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Tlr4 Signaling ◽

F Protein ◽

Terminal Domain ◽

Syncytial Virus ◽

Tlr4 Activation

ABSTRACTRespiratory syncytial virus (RSV) is a leading cause of infant mortality worldwide. Toll-like receptor 4 (TLR4), a signaling receptor for structurally diverse microbe-associated molecular patterns, is activated by the RSV fusion (F) protein and by bacterial lipopolysaccharide (LPS) in a CD14-dependent manner. TLR4 signaling by LPS also requires the presence of an additional protein, MD-2. Thus, it is possible that F protein-mediated TLR4 activation relies on MD-2 as well, although this hypothesis has not been formally tested. LPS-free RSV F protein was found to activate NF-κB in HEK293T transfectants that express wild-type (WT) TLR4 and CD14, but only when MD-2 was coexpressed. These findings were confirmed by measuring F-protein-induced interleukin 1β (IL-1β) mRNA in WT versus MD-2−/−macrophages, where MD-2−/−macrophages failed to show IL-1β expression upon F-protein treatment, in contrast to the WT. BothRhodobacter sphaeroidesLPS and synthetic E5564 (eritoran), LPS antagonists that inhibit TLR4 signaling by binding a hydrophobic pocket in MD-2, significantly reduced RSV F-protein-mediated TLR4 activity in HEK293T-TLR4–CD14–MD-2 transfectants in a dose-dependent manner, while TLR4-independent NF-κB activation by tumor necrosis factor alpha (TNF-α) was unaffected.In vitrocoimmunoprecipitation studies confirmed a physical interaction between native RSV F protein and MD-2. Further, we demonstrated that the N-terminal domain of the F1 segment of RSV F protein interacts with MD-2. These data provide new insights into the importance of MD-2 in RSV F-protein-mediated TLR4 activation. Thus, targeting the interaction between MD-2 and RSV F protein may potentially lead to novel therapeutic approaches to help control RSV-induced inflammation and pathology.IMPORTANCEThis study shows for the first time that the fusion (F) protein of respiratory syncytial virus (RSV), a major cause of bronchiolitis and death, particularly in infants and young children, physically interacts with the Toll-like receptor 4 (TLR4) coreceptor, MD-2, through its N-terminal domain. We show that F protein-induced TLR4 activation can be blocked by lipid A analog antagonists. This observation provides a strong experimental rationale for testing such antagonists in animal models of RSV infection for potential use in people.

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