Activation of ASC Inflammasome Driven by Toll-Like Receptor 4 Contributes to Host Immunity against Rickettsial Infection

ABSTRACT Rickettsiae are cytosolically replicating, obligately intracellular bacteria causing human infections worldwide with potentially fatal outcomes. We previously showed that Rickettsia australis activates ASC inflammasome in macrophages. In the present study, host susceptibility of ASC inflammasome-deficient mice to R. australis was significantly greater than that of C57BL/6 (B6) controls and was accompanied by increased rickettsial loads in various organs. Impaired host control of R. australis in vivo in ASC−/− mice was associated with dramatically reduced levels of interleukin 1β (IL-1β), IL-18, and gamma interferon (IFN-γ) in sera. The intracellular concentrations of R. australis in bone marrow-derived macrophages (BMMs) of TLR4−/− and ASC−/− mice were significantly greater than those in BMMs of B6 controls, highlighting the important role of inflammasome and these molecules in controlling rickettsiae in macrophages. Compared to B6 BMMs, TLR4−/− BMMs failed to secrete a significant level of IL-1β and had reduced expression levels of pro-IL-1β in response to infection with R. australis, suggesting that rickettsiae activate ASC inflammasome via a Toll-like receptor 4 (TLR4)-dependent mechanism. Further mechanistic studies suggest that the lipopolysaccharide (LPS) purified from R. australis together with ATP stimulation led to cleavage of pro-caspase-1 and pro-IL-1β, resulting in TLR4-dependent secretion of IL-1β. Taken together, these observations indicate that activation of ASC inflammasome, most likely driven by interaction of TLR4 with rickettsial LPS, contributes to host protective immunity against R. australis. These findings provide key insights into defining the interactions of rickettsiae with the host innate immune system.

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Systems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4+ T Cell Responses during Chronic Helicobacter pylori Infection

mBio ◽

10.1128/mbio.01243-14 ◽

2014 ◽

Vol 5 (4) ◽

Cited By ~ 36

Author(s):

Adria Carbo ◽

Danyvid Olivares-Villagómez ◽

Raquel Hontecillas ◽

Josep Bassaganya-Riera ◽

Rupesh Chaturvedi ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

T Cell ◽

Wild Type ◽

Content Type ◽

Interleukin 21 ◽

H Pylori ◽

Deficient Mice

ABSTRACTThe development of gastritis duringHelicobacter pyloriinfection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa duringH. pyloriinfection, we combined mathematical modeling of CD4+T cell differentiation within vivomechanistic studies. We infected IL-21-deficient and wild-type mice withH. pyloristrain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. ChronicallyH. pylori-infected IL-21-deficient mice had higherH. pyloricolonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. Thesein vivodata were used to calibrate anH. pyloriinfection-dependent, CD4+T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-γ) and IL-17 during chronicH. pyloriinfection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4+splenocyte-specifictbx21androrcexpression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4+T cell-specific IL-10 expression inH. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronicH. pyloriinfection in a STAT1- and STAT3-dependent manner, therefore playing a major role controllingH. pyloriinfection and gastritis.IMPORTANCEHelicobacter pyloriis the dominant member of the gastric microbiota in more than 50% of the world’s population.H. pyloricolonization has been implicated in gastritis and gastric cancer, as infection withH. pyloriis the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis duringH. pyloriinfection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized withH. pylorias an alternative to aggressive antibiotics.

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In Vivo Evidence for a Role of Toll-Like Receptor 4 in the Development of Intimal Lesions

Circulation ◽

10.1161/01.cir.0000032146.75113.ee ◽

2002 ◽

Vol 106 (15) ◽

pp. 1985-1990 ◽

Cited By ~ 172

Author(s):

Aryan Vink ◽

Arjan H. Schoneveld ◽

Jelger J. van der Meer ◽

Ben J. van Middelaar ◽

Joost P.G. Sluijter ◽

...

Keyword(s):

Toll Like Receptor ◽

Toll Like Receptor 4

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Role of Toll-Like Receptor 4 in Intimal Foam Cell Accumulation in Apolipoprotein E–Deficient Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.110.210971 ◽

2011 ◽

Vol 31 (1) ◽

pp. 50-57 ◽

Cited By ~ 85

Author(s):

Mie Higashimori ◽

Jeffrey B. Tatro ◽

Kathryn J. Moore ◽

Michael E. Mendelsohn ◽

Jonas B. Galper ◽

...

Keyword(s):

Apolipoprotein E ◽

Foam Cell ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Cell Accumulation ◽

Deficient Mice

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Role of Toll Interleukin-1 Receptor (IL-1R) 8, a Negative Regulator of IL-1R/Toll-Like Receptor Signaling, in Resistance to Acute Pseudomonas aeruginosa Lung Infection

Infection and Immunity ◽

10.1128/iai.05695-11 ◽

2011 ◽

Vol 80 (1) ◽

pp. 100-109 ◽

Cited By ~ 30

Author(s):

Tania Véliz Rodriguez ◽

Federica Moalli ◽

Nadia Polentarutti ◽

Moira Paroni ◽

Eduardo Bonavita ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Interleukin 1 ◽

Bacterial Load ◽

Lung Infection ◽

Negative Regulator ◽

Current Evidence ◽

Toll Like Receptor ◽

Content Type ◽

Deficient Mice

ABSTRACTToll interleukin-1 receptor (IL-1R) 8 (TIR8), also known as single Ig IL-1 receptor (IL-R)-related molecule, or SIGIRR, is a member of the IL-1R-like family, primarily expressed by epithelial cells. Current evidence suggests that TIR8 plays a nonredundant role as a negative regulatorin vivounder different inflammatory conditions that are dependent on IL-R and Toll-like receptor (TLR) activation. In the present study, we examined the role of TIR8 in innate resistance to acute lung infections caused byPseudomonas aeruginosa, a Gram-negative pathogen responsible for life-threatening infections in immunocompromised individuals and cystic fibrosis patients. We show that Tir8 deficiency in mice was associated with increased susceptibility to acuteP. aeruginosainfection, in terms of mortality and bacterial load, and to exacerbated local and systemic production of proinflammatory cytokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], IL-1β, and IL-6) and chemokines (CXCL1, CXCL2, and CCL2). It has been reported that host defense againstP. aeruginosaacute lung infection can be improved by blocking IL-1 since exaggerated IL-1β production may be harmful for the host in this infection. In agreement with these data, IL-1RI deficiency rescues the phenotype observed in Tir8-deficient mice: in Tir8−/−IL-1RI−/−double knockout mice we observed higher survival rates, enhanced bacterial clearance, and reduced levels of local and systemic cytokine and chemokine levels than in Tir8-deficient mice. These results suggest that TIR8 has a nonredundant effect in modulating the inflammation caused byP. aeruginosa, in particular, by negatively regulating IL-1RI signaling, which plays a major role in the pathogenesis of this infectious disease.

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TREM2, Driving the Microglial Polarization, Has a TLR4 Sensitivity Profile After Subarachnoid Hemorrhage

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.693342 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yangchun Hu ◽

Chao Li ◽

Xiaojian Wang ◽

Weiwei Chen ◽

Yu Qian ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Neuroprotective Effect ◽

Neurological Dysfunction ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Microglial Polarization ◽

The Relationship

Increasing evidence suggests that triggering receptor expressed on myeloid cells 2 (TREM2) is implicated in the pathophysiology of neuroinflammation. The aim here was to investigate the neuroprotective role of TREM2 and its regulatory mechanism after subarachnoid hemorrhage (SAH). TREM2 siRNA was administered to measure the detrimental role of TREM2 in mediating microglial polarization in vivo and in vitro after experimental SAH. The relationship between Toll-like receptor 4 (TLR4) signaling and TREM2 was further explored. The soluble TREM2 from the cerebrospinal fluid (CSF) of patients with SAH was detected. The results showed that TREM2 mainly located in the microglia and presented a markedly delayed elevation after SAH. TREM2 knockdown triggered increased pro-inflammatory productions, aggravated microglial activities, and further exacerbated neurological dysfunction after SAH. Significantly, TLR4 knockout increased the expression of TREM2, accompanied by ameliorated neuroinflammation and improved neurological function. Corresponding to different clinical Hunt–Hess grades, obviously enhanced accumulation of soluble TREM2 was detected in the CSF of patients with SAH. TREM2 played a pivotal role in mediating microglial polarization after SAH, and the neuroprotective effect of TREM2 might be potentially suppressed by the hyperactive TLR4 in the early phase of SAH. Pharmacological targeting of TREM2 may be a promising strategy for SAH therapy.

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In Vivo Expression of Proinflammatory Mediators in the Adult Heart after Endotoxin Administration: The Role of Toll‐Like Receptor–4

The Journal of Infectious Diseases ◽

10.1086/320712 ◽

2001 ◽

Vol 183 (11) ◽

pp. 1617-1624 ◽

Cited By ~ 158

Author(s):

Georg Baumgarten ◽

Pascal Knuefermann ◽

Naoki Nozaki ◽

Natarajan Sivasubramanian ◽

Douglas L. Mann ◽

...

Keyword(s):

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Adult Heart ◽

Endotoxin Administration ◽

Proinflammatory Mediators ◽

In Vivo Expression

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Aggravated Liver Injury but Attenuated Inflammation in PTPRO-Deficient Mice Following LPS/D-GaIN Induced Fulminant Hepatitis

Cellular Physiology and Biochemistry ◽

10.1159/000430346 ◽

2015 ◽

Vol 37 (1) ◽

pp. 214-224 ◽

Cited By ~ 8

Author(s):

Xiaochen Wang ◽

Shushan Yan ◽

Donghua Xu ◽

Jun Li ◽

Yu Xie ◽

...

Keyword(s):

Liver Injury ◽

Fulminant Hepatitis ◽

Feedback Regulation ◽

Adaptive Immune ◽

Hepatic Cells ◽

Ifn Γ ◽

Deficient Mice

Background/Aims: Critical roles of PTPRO and TLR4 have been implicated in hepatocellular carcinoma. However, little is known about their modifying effects on inflammation-related diseases in liver, particularly fulminant hepatitis (FH). We aim to investigate the potential role of PTPRO and its interaction with TLR4 in LPS/D-GaIN induced FH. Methods: A LPS/D-GaIN induced mouse FH model was used. RAW264.7 cells were transfected with PTPRO over-expressed lentiviral plasmids for further investigation. Results: The mortality of PTPRO KO mice is higher than WT mice after LPS/D-GaIN administration. Aggravated liver injury was demonstrated by increased level of serous ALT and AST and numerous hepatic cells death in PTPRO KO mice following LPS/D-GaIN administration. Interestingly, inflammation was attenuated in PTPRO-deficient mice following LPS/D-GaIN administration, which was suggested by decreased inflammatory cytokines (TNF-a, IFN-γ, IL-1ß, IL-6, IL-17A and IL-12) and cells infiltrating into spleen (CD3+IFN-γ+ cells, CD3+TNF-a+ cells, F4/80+/TLR4+ cells). A feedback regulation between PTPRO and TLR4 dependent on NF-γB signaling pathway was demonstrated in vivo and in vitro. Conclusion: PTPRO plays an important role in FH by interacting with TLR4. The crosstalk between PTPRO and TLR4 is a novel bridge linking innate immune and adaptive immune in acute liver injury.

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The Absence of Toll-Like Receptor 4 Signaling in C3H/HeJ Mice Predisposes Them to Overwhelming Rickettsial Infection and Decreased Protective Th1 Responses

Infection and Immunity ◽

10.1128/iai.00311-08 ◽

2008 ◽

Vol 76 (8) ◽

pp. 3717-3724 ◽

Cited By ~ 39

Author(s):

Jeffrey M. Jordan ◽

Michael E. Woods ◽

Juan Olano ◽

David H. Walker

Keyword(s):

Rickettsia Conorii ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Necrosis Factor Alpha ◽

Tlr4 Signaling ◽

Rickettsial Infections ◽

Factor Alpha ◽

Intravenous Inoculation

ABSTRACT The importance of toll-like receptor 4 (TLR4) in immunity to rickettsiae remains elusive. To investigate the role of TLR4 in protection against rickettsioses, we utilized C3H/HeJ mice, which are naturally defective in TLR4 signaling, and compared the responses of C3H/HeN and C3H/HeJ mice following intravenous inoculation with Rickettsia conorii. Mice genetically defective in TLR4 signaling developed overwhelming, fatal rickettsial infections when given an inoculum that was nonfatal for TLR4-competent mice. In addition, mice lacking the ability to signal through TLR4 had significantly greater rickettsial burdens in vivo. Moreover, we observed greater concentrations of the cytokines interleukin 6 (IL-6), tumor necrosis factor alpha, IL-12p40, IL-12p70, and IL-17 in the sera of mice with intact TLR4 function as well as significantly greater quantities of activated CD4+ and CD8+ T lymphocytes. Additionally, we also observed that Th17 cells were present only in TLR4-competent mice, suggesting an important role for TLR4 ligation in the activation of this subset. In agreement with these data, we also observed significantly greater percentages of immunosuppressive regulatory T cells in the spleen during infection in TLR4-defective mice. Together, these data demonstrate that, while rickettsiae do not contain endotoxic lipopolysaccharide, they nevertheless initiate TLR4-specific immune responses, and these responses are important in protection.

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The role of Toll-like receptor 9 in a murine model of Cryptococcus gattii infection

Scientific Reports ◽

10.1038/s41598-021-80959-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Elias Barbosa da Silva-Junior ◽

Luan Firmino-Cruz ◽

Joyce Cristina Guimarães-de-Oliveira ◽

Juliana Valente Rodrigues De-Medeiros ◽

Danielle de Oliveira Nascimento ◽

...

Keyword(s):

Immune Response ◽

Dna Interaction ◽

Cryptococcus Gattii ◽

Host Immunity ◽

Yeast Cells ◽

Toll Like Receptor ◽

Knock Out ◽

Ifn Γ

AbstractToll-like receptor 9 (TLR9) is crucial to the host immune response against fungi, such as Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans, but its importance in Cryptococcus gattii infection is unknown. Our study aimed to understand the role of TLR9 during the course of experimental C. gattii infection in vivo, considering that the cryptococcal DNA interaction with the receptor could contribute to host immunity even in an extremely susceptible model. We inoculated C57BL/6 (WT) and TLR9 knock-out (TLR9−/−) mice intratracheally with 104C. gattii yeast cells. TLR9−/− mice had a higher mortality rate compared to WT mice and more yeast cells that had abnormal size, known as titan cells, in the lungs. TLR9−/− mice also had a greater number of CFUs in the spleen and brain than WT mice, in addition to having lower levels of IFN-γ and IL-17 in the lung. With these markers of aggressive cryptococcosis, we can state that TLR9−/− mice are more susceptible to C. gattii, probably due to a mechanism associated with the decrease of a Th1 and Th17-type immune response that promotes the formation of titan cells in the lungs. Therefore, our results indicate the participation of TLR9 in murine resistance to C. gattii infection.

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Platelet-bound lipopolysaccharide enhances Fc receptor–mediated phagocytosis of IgG-opsonized platelets

Blood ◽

10.1182/blood-2006-12-062695 ◽

2007 ◽

Vol 109 (11) ◽

pp. 4803-4805 ◽

Cited By ~ 91

Author(s):

John W. Semple ◽

Rukhsana Aslam ◽

Michael Kim ◽

Edwin R. Speck ◽

John Freedman

Keyword(s):

Flow Cytometry ◽

Toll Like Receptor ◽

Autoimmune Thrombocytopenia ◽

Toll Like Receptor 4 ◽

Platelet Destruction ◽

Gram Negative ◽

Synergistic Increase

Abstract Platelets express Toll-like receptor 4 (TLR4), and this has been shown to be responsible for the thrombocytopenia induced by lipopolysaccharide (LPS) administration in vivo. We studied the role of LPS in mediating platelet phagocytosis by THP-1 cells in vitro by flow cytometry. Opsonization of platelets with an IgG monoclonal (W6/32) antibody or with IgG autoantibody-positive sera from patients with autoimmune thrombocytopenia (AITP) significantly enhanced platelet phagocytosis (P < .001). In contrast, platelet phagocytosis did not occur if platelets were bound with only LPS. If, however, the LPS-bound platelets were also opsonized with either W6/32 or autoantibody-positive sera with titers greater than 4, there was a significant and synergistic increase in Fc-dependent platelet phagocytosis (P < .001, P = .003, P = .048, and P = .047). These results suggest that, in the presence of antiplatelet antibodies, bacterial products can significantly alter platelet phagocytosis, and this may have relevance to how Gram-negative infections enhance platelet destruction in some patients with AITP.

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