scholarly journals A46 THE INFLAMMATORY CASPASES COORDINATE MUCOSAL RESTRICTION OF SALMONELLA THROUGH THE EPITHELIAL-INTRINSIC INFLAMMASOME AND IL-22 DRIVEN MUCIN SECRETION

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 54-55
Author(s):  
S M Crowley ◽  
J M Allaire ◽  
X Han ◽  
F A Graef ◽  
M Stahl ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Neutralizing Antibody ◽  
Immune Defense ◽  
Enteric Pathogen ◽  
Mucosal Defense ◽  
Innate Defense ◽  
Systemic Spread ◽  
Inflammatory Caspases ◽  
Deficient Mice

Abstract Background Intestinal epithelial cells (IECs) are located at the interface between the gut lumen and the underlying mucosal defense system. Here, they play a central role in the coordination of intestinal homeostasis, tempering pro-inflammatory responses but remaining rapidly responsive to noxious stimuli such as enteric pathogens. One early response mechanism by which IECs engage in immune defense is through the activation of the inflammasome which mobilizes the inflammatory caspases; caspase-1 and -11. Aims Here, we investigated the role of the inflammasome in overall mucosal defense against the enteric pathogen Salmonella enterica serovar Typhimurium. Methods Streptomycin-pretreated C57BL/6 (wildtype), Casp1/11 deficient (−/−), Casp1−/− and Casp11−/− mice were orally infected with Salmonella and burdens determined in intestinal tissues at 18h post infection (p.i.). Results Increased pathogen loads were observed for all caspase-deficient mice compared to wildtype, which correlated with increased IEC intracellular Salmonella burdens. Interestingly, despite increased bacterial loads, pathology scores for all inflammatory caspase mice were decreased, especially with regard to ‘IEC damage’ and ‘goblet cell loss’. To determine if the increased burdens were due to the loss of IEC-intrinsic inflammasomes, enteroid monolayers were derived and infected with Salmonella. This revealed significantly increased intracellular burdens in caspase-deficient monolayers as compared to wildtype, in concert with a marked decrease in IEC shedding and cell death. Peak inflammatory caspase activity was displayed in shedding wildtype IECs, suggesting the IEC-intrinsic inflammasome restricts Salmonella infection through infected IEC expulsion. The role of inflammasome signaling in acute mucosal defense was also examined. Wildtype tissue demonstrated a dramatic increase in mucus thickness (as evaluated by Muc2 immunostaining) and antimicrobial Reg3γ and β lectin transcript levels compared to caspase-deficient mice. Mucin release and Reg3 induction has been previously linked to IL-22, therefore we measured IL-22 expression and observed increased secretion in infected wildtype mice compared to Casp1/11−/−. This correlated with increased cecal infiltration of IL-22 producing ILC3 and NK T-cells. When infected mice were treated with IL-22 neutralizing antibody, this increased Salmonella burdens and decreased infection-induced mucus secretion, while no differences were observed in Casp1/11−/− treated with neutralizing antibody or isotype control. Conclusions Therefore the intestinal epithelium utilizes inflammasome signaling to coordinate multiple layers of innate defense at the gut mucosal surface to ultimately restrict enteric pathogen infections and their systemic spread. Funding Agencies CCC, CIHR, NRCUBC

scholarly journals Role of MDA5 in regulating CXCL10 expression induced by TLR3 signaling in human rheumatoid fibroblast-like synoviocytes

2021 ◽  
Author(s):  
Tatsuro Saruga ◽  
Tadaatsu Imaizumi ◽  
Shogo Kawaguchi ◽  
Kazuhiko Seya ◽  
Tomoh Matsumiya ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Neutralizing Antibody ◽  
Poly I:C ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Inflammatory Reactions ◽  
Polyinosinic:Polycytidylic Acid ◽  
Tlr3 Signaling ◽  
Fibroblast Like Synoviocytes

AbstractC-X-C motif chemokine 10 (CXCL10) is an inflammatory chemokine and a key molecule in the pathogenesis of rheumatoid arthritis (RA). Melanoma differentiation-associated gene 5 (MDA5) is an RNA helicase that plays a role in innate immune and inflammatory reactions. The details of the regulatory mechanisms of CXCL10 production and the precise role of MDA5 in RA synovitis have not been fully elucidated. The aim of this study was to examine the role of MDA5 in regulating CXCL10 expression in cultured human rheumatoid fibroblast-like synoviocytes (RFLS). RFLS was stimulated with Toll-like receptor 3 (TLR3) ligand polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA mimetic. Expression of interferon beta (IFN-β), MDA5, and CXCL10 was measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assay. A neutralizing antibody of IFN-β and siRNA-mediated MDA5 knockdown were used to determine the role of these molecules in regulating CXCL10 expression downstream of TLR3 signaling in RFLS. Poly I:C induced IFN-β, MDA5, and CXCL10 expression in a concentration- and time-dependent manner. IFN-β neutralizing antibody suppressed the expression of MDA5 and CXCL10, and knockdown of MDA5 decreased a part of CXCL10 expression (p < 0.001). The TLR3/IFN-β/CXCL10 axis may play a crucial role in the inflammatory responses in RA synovium, and MDA5 may be partially involved in this axis.

A Role of Plasminogen in Atherosclerosis and Restenosis Models in Mice

1999 ◽  
Vol 82 (S 01) ◽  
pp. 4-7 ◽  
Author(s):  
Victoria A. Ploplis ◽  
Steven Busuttil ◽  
Peter Carmeliet ◽  
Desire Collen ◽  
Edward F. Plow
Keyword(s):  
Vessel Wall ◽  
Inflammatory Responses ◽  
Leukocyte Migration ◽  
Early Event ◽  
Macrophage Migration ◽  
Murine Models ◽  
Response Models ◽  
Deficient Mice

SummaryIn addition to its preeminent role in fibrinolysis, the plasminogen system is believed to play a key role in mediating cell migration. Leukocyte migration into the vessel wall is a key and early event in the development of the lesions of atherosclerosis and restenosis, pathologies which may be viewed as specific examples of vascular inflammatory responses. The development of mice in which the plasminogen gene has been inactivated affords an opportunity to test the contribution of plasminogen in leukocyte migration during in vivo. This article summarizes recent studies conducted in murine models of the inflammatory repsonse, restenosis and atherosclerosis in which leukocyte migration, and in particular monocyte/macrophage migration, has been evaluated in plasminogen-deficient mice. Recruitment of these cells through the vessel wall in inflammatory response models and into the vessel wall in restenosis and transplant atherosclerosis models is substantially blunted. These data implicate plasminogen in the migration of leukocytes in these murine models. With the numerous correlations between components and/or activation of the plasminogen system in restenosis and atherosclerosis, these results also support a role of plasminogen in the corresponding human pathologies.

scholarly journals The Role of IL-33 in Host Response toCandida albicans

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
C. Rodríguez-Cerdeira ◽  
A. Lopez-Bárcenas ◽  
B. Sánchez-Blanco ◽  
R. Arenas
Keyword(s):  
Defense Mechanisms ◽  
Fungal Pathogens ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Case Reports ◽  
Pathogenic Fungi ◽  
Cell Types ◽  
Immune Defense ◽  
Beneficial Role

Background. Interleukin (IL) 33 is a recently identified pleiotropic cytokine that influences the activity of multiple cell types and orchestrates complex innate and adaptive immune responses.Methods. We performed an extensive review of the literature published between 2005 and 2013 on IL-33 and related cytokines, their functions, and their regulation of the immune system followingCandida albicanscolonization. Our literature review included cross-references from retrieved articles and specific data from our own studies.Results. IL-33 (IL-1F11) is a recently identified member of the IL-1 family of cytokines. Accumulating evidence suggests a pivotal role of the IL-33/ST2 axis in host immune defense against fungal pathogens, includingC. albicans. IL-33 induces a Th2-type inflammatory response and activates both innate and adaptive immunity. Studies in animal models have shown that Th2 inflammatory responses have a beneficial role in immunity against gastrointestinal and systemic infections byCandidaspp.Conclusions. This review summarizes the most important clinical studies and case reports describing the beneficial role of IL-33 in immunity and host defense mechanisms against pathogenic fungi. The finding that the IL-33/ST2 axis is involved in therapeutic target has implications for the prevention and treatment of inflammatory diseases, including acute or chronic candidiasis.

Abstract 307: Role of Epsins in Regulating LPS-Induced Sepsis

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Satish Pasula ◽  
Megan L Brophy ◽  
Kandice L Tessneer ◽  
Scott Hahn ◽  
John McManus ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Tissue Injury ◽  
Lethal Dose ◽  
Surface Protein ◽  
Inflammatory Conditions ◽  
Fundamental Information ◽  
Subsequent Degradation ◽  
Surface Protein Expression ◽  
Deficient Mice

Background: Sepsis is caused by a deleterious host response to infection, which is primarily responsible for further injury of host tissue and cause of organ dysfunction. However, the underlying regulatory mechanisms are still not fully understood. Our goal is to define the novel role of epsins in regulating sepsis. Methods and Results: We engineered global (iDKO) and endothelial cell-specific (EC-iDKO) epsin deficient mice. When treated with lethal dose of LPS, epsin deficient mice were completely protected from LPS-induced septic death. These mice also exhibited decreased expression of tissue damage biomarkers and recruitment of neutrophils and macrophages to lungs compared to wild type (WT) suggesting that epsin deficiency mitigates sepsis induced tissue injury. Epsin deficiency further reduced expression of proinflammatory cytokines and adhesion molecules in the lungs suggesting that loss of epsin attenuates LPS-induced inflammatory responses. TAT complex production was also decreased in iDKO mice compared to WT indicating diminished coagulation and thrombin production. Knocking down of epsins in HUVECs resulted in reduced cell surface Tissue Factor (TF) expression. Loss of epsin in mice protected against loss of Thrombomodulin (TM), which is downregulated by sepsis. Mechanistically, loss of epsin inhibited LPS-induced TM internalization, while LPS treatment induced the ubiquitination of TM. Furthermore, co-IP of full length epsin 1 or epsin 1 without the UIM domain and TM demonstrated that UIM is required for the interaction between epsin 1 and TM. Collectively, we show that epsin-deficiency upregulates TM surface protein expression by preventing its internalization and subsequent degradation and inhibits heightened TF expression and activation under chronic inflammatory conditions such as that induced by LPS exposure. Conclusions: Our findings demonstrate that epsins play a key role in regulating coagulation and provide fundamental information on the modulation of the ratio of TM/TF in various thrombotic diseases including sepsis. Furthermore, we demonstrate loss of epsin protects mice against LPS-induced sepsis, suggesting a crucial role for epsins in promoting the development of LPS-induced sepsis.

scholarly journals Role of the Classical Pathway of Complement Activation in Experimentally Induced Polymicrobial Peritonitis

2001 ◽  
Vol 69 (12) ◽  
pp. 7304-7309 ◽  
Author(s):  
Ilhan Celik ◽  
Cordula Stover ◽  
Marina Botto ◽  
Steffen Thiel ◽  
Sotiria Tzima ◽  
...  
Keyword(s):  
Complement System ◽  
Complement Activation ◽  
Immune Defense ◽  
Classical Pathway ◽  
Complement Factor ◽  
Wild Type ◽  
Factor B ◽  
The Complement System ◽  
Deficient Mice

ABSTRACT The complement system and the natural antibody repertoire provide a critical first-line defense against infection. The binding of natural antibodies to microbial surfaces opsonizes invading microorganisms and activates complement via the classical pathway. Both defense systems cooperate within the innate immune response. We studied the role of the complement system in the host defense against experimental polymicrobial peritonitis using mice lacking either C1q or factor B and C2. The C1q-deficient mice lacked the classical pathway of complement activation. The factor B- and C2-deficient mice were known to lack the classical and alternative pathways, and we demonstrate here that these mice also lacked the lectin pathway of complement activation. Using inoculum doses adjusted to cause 42% mortality in the wild-type strain, none of the mice deficient in the three activation routes of complement (factor B and C2 deficient) survived (mortality of 100%). Mortality in mice deficient only in the classical pathway of complement activation (C1q deficient) was 83%. Application of further dilutions of the polymicrobial inoculum showed a dose-dependent decrease of mortality in wild-type controls, whereas no changes in mortality were observed in the two gene-targeted strains. These results demonstrate that the classical activation pathway is required for an effective antimicrobial immune defense in polymicrobial peritonitis and that, in the infection model used, the remaining antibody-independent complement activation routes (alternative and lectin pathways) provide a supporting line of defense to gain residual protection in classical pathway deficiency.

scholarly journals Sexual dimorphism of monocyte transcriptome in individuals with chronic low-grade inflammation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jisun So ◽  
Albert K. Tai ◽  
Alice H. Lichtenstein ◽  
Dayong Wu ◽  
Stefania Lamon-Fava
Keyword(s):  
Sexual Dimorphism ◽  
Cell Activation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Immune Defense ◽  
Low Grade ◽  
Immune Functions ◽  
Blood Monocytes ◽  
Low Grade Inflammation

AbstractSexual dimorphism in the immune system is evidenced by a higher prevalence of autoimmune diseases in women and higher susceptibility to infectious diseases in men. However, the molecular basis of these sex-based differences is not fully understood. We have characterized the transcriptome profiles of peripheral blood monocytes from males and postmenopausal females with chronic low-grade inflammation. We identified 41 sexually differentially expressed genes [adjusted p value (FDR) < 0.1], including genes involved in immune cell activation (e.g., CEACAM1, FCGR2B, and SLAMF7) and antigen presentation (e.g., AIM2, CD1E, and UBA1) with a higher expression in females than males. Moreover, signaling pathways of immune or inflammatory responses, including interferon (IFN) signaling [z-score = 2.45, -log(p) = 3.88], were found to be more upregulated in female versus male monocytes, based on a set of genes exhibiting sex-biased expression (p < 0.03). The contribution of IFN signaling to the sexual transcriptional differences was further confirmed by direct comparisons of the monocyte sex-biased genes with IFN signature genes (ISGs) that were previously curated in mouse macrophages. ISGs showed a greater overlap with female-biased genes than male-biased genes and a higher overall expression in female than male monocytes, particularly for the genes of antiviral and inflammatory responses to IFN. Given the role of IFN in immune defense and autoimmunity, our results suggest that sexual dimorphism in immune functions may be associated with more priming of innate immune pathways in female than male monocytes. These findings highlight the role of sex on the human immune transcriptome.

scholarly journals Pigment Nephropathy: Novel Insights into Inflammasome-Mediated Pathogenesis

2019 ◽  
Author(s):  
Kurt T. K. Giuliani ◽  
Andrew J. Kassianos ◽  
Helen Healy ◽  
Pedro F. H. Gois
Keyword(s):  
Nlrp3 Inflammasome ◽  
Potential Role ◽  
Inflammatory Responses ◽  
Receptor Protein ◽  
Interleukin 18 ◽  
Nucleotide Binding Domain ◽  
Renal Vasoconstriction ◽  
Pigment Nephropathy ◽  
Inflammatory Caspases

Pigment nephropathy is an acute decline in renal function following the deposition of endogenous haem-containing proteins in the kidneys. Haem pigments such as myoglobin and haemoglobin are filtered by glomeruli and absorbed by the proximal tubules. They cause renal vasoconstriction, tubular obstruction, increased oxidative stress and inflammation. Haem is associated with inflammation in sterile and infectious conditions, contributing to the pathogenesis of many disorders such as rhabdomyolysis and haemolytic diseases. In fact, haem appears to be a signaling molecule that is able to activate the inflammasome pathway. Recent studies highlight a pathogenic function for haem in triggering inflammatory responses through the activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. Among the inflammasome multiprotein complexes, the NLRP3 inflammasome has been the most widely characterized as a trigger of inflammatory caspases and the maturation of interleukin-18 and -1&beta;. In the present review, we discuss the latest evidence on the importance of inflammasome-mediated inflammation in pigment nephropathy. Finally, we highlight the potential role of inflammasome inhibitors in the prophylaxis and treatment of pigment nephropathy.

scholarly journals Pigment Nephropathy: Novel Insights into Inflammasome-Mediated Pathogenesis

2019 ◽  
Vol 20 (8) ◽  
pp. 1997 ◽  
Author(s):  
Kurt T. K. Giuliani ◽  
Andrew J. Kassianos ◽  
Helen Healy ◽  
Pedro H. F. Gois
Keyword(s):  
Nlrp3 Inflammasome ◽  
Potential Role ◽  
Inflammatory Responses ◽  
Receptor Protein ◽  
Nucleotide Binding Domain ◽  
Renal Vasoconstriction ◽  
Signalling Molecule ◽  
Pigment Nephropathy ◽  
Inflammatory Caspases

Pigment nephropathy is an acute decline in renal function following the deposition of endogenous haem-containing proteins in the kidneys. Haem pigments such as myoglobin and haemoglobin are filtered by glomeruli and absorbed by the proximal tubules. They cause renal vasoconstriction, tubular obstruction, increased oxidative stress and inflammation. Haem is associated with inflammation in sterile and infectious conditions, contributing to the pathogenesis of many disorders such as rhabdomyolysis and haemolytic diseases. In fact, haem appears to be a signalling molecule that is able to activate the inflammasome pathway. Recent studies highlight a pathogenic function for haem in triggering inflammatory responses through the activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. Among the inflammasome multiprotein complexes, the NLRP3 inflammasome has been the most widely characterized as a trigger of inflammatory caspases and the maturation of interleukin-18 and -1β. In the present review, we discuss the latest evidence on the importance of inflammasome-mediated inflammation in pigment nephropathy. Finally, we highlight the potential role of inflammasome inhibitors in the prophylaxis and treatment of pigment nephropathy.

scholarly journals The Scavenger Receptor MARCO Is Required for Lung Defense against Pneumococcal Pneumonia and Inhaled Particles

2004 ◽  
Vol 200 (2) ◽  
pp. 267-272 ◽  
Author(s):  
Mohamed Arredouani ◽  
Zhiping Yang ◽  
YaoYu Ning ◽  
Guozhong Qin ◽  
Raija Soininen ◽  
...  
Keyword(s):  
Pneumococcal Pneumonia ◽  
Inflammatory Responses ◽  
Scavenger Receptor ◽  
Pneumococcal Infection ◽  
Innate Defense ◽  
Inhaled Particles ◽  
Lung Defense

Alveolar macrophages (AMs) express the class A scavenger receptor macrophage receptor with collagenous structure (MARCO), but its role in vivo in lung defense against bacteria and environmental particles has not been studied. We used MARCO-deficient mice to directly test the in vivo role of AM MARCO in innate defense against pneumococcal infection and environmental particles. In a murine model of pneumococcal pneumonia, MARCO−/− mice displayed an impaired ability to clear bacteria from the lungs, increased pulmonary inflammation and cytokine release, and diminished survival. In vitro binding of Streptococcus pneumoniae and in vivo uptake of unopsonized particles by MARCO−/− AMs were dramatically impaired. MARCO−/− mice treated with the “inert” environmental particle TiO2 showed enhanced inflammation and chemokine expression, indicating that MARCO-mediated clearance of inert particles by AMs prevents inflammatory responses otherwise initiated by other lung cells. Our findings point to an important role of MARCO in mounting an efficient and appropriately regulated innate immune response against inhaled particles and airborne pathogens.

scholarly journals IL-17 Aggravates Pseudomonas aeruginosa Airway Infection in Acute Exacerbations of Chronic Obstructive Pulmonary Disease

2022 ◽  
Vol 12 ◽  
Author(s):  
Fengming Ding ◽  
Lei Han ◽  
Qiang Fu ◽  
Xinxin Fan ◽  
Rong Tang ◽  
...  
Keyword(s):  
Mouse Models ◽  
Inflammatory Cytokine ◽  
Inflammatory Responses ◽  
Neutralizing Antibody ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Airway Infection ◽  
Copd Patients ◽  
Acute Exacerbations

Pseudomonas aeruginosa airway infection increases risks of exacerbations and mortality in chronic obstructive pulmonary disease (COPD). We aimed to elucidate the role of IL-17 in the pathogenesis. We examined the expression and influences of IL-23/IL-17A in patients with stable COPD (n = 33) or acute COPD exacerbations with P. aeruginosa infection (n = 34). A mouse model of COPD (C57BL/6) was used to investigate the role of IL-17A in host inflammatory responses against P. aeruginosa infection through the application of IL-17A–neutralizing antibody or recombinant IL-17A. We found that P. aeruginosa infection increased IL-23/17A signaling in lungs of both COPD patients and COPD mouse models. When COPD mouse models were treated with neutralizing antibody targeting IL-17A, P. aeruginosa induced a significantly less polymorphonuclear leukocyte infiltration and less bacterial burden in their lungs compared to those of untreated counterparts. The lung function was also improved by neutralizing antibody. Furthermore, IL-17A-signaling blockade significantly reduced the expression of pro-inflammatory cytokine IL-1β, IL-18, TNF-α, CXCL1, CXCL15 and MMP-9, and increased the expression of anti-inflammatory cytokine IL-10 and IL-1Ra. The application of mouse recombinant IL-17A exacerbated P. aeruginosa-mediated inflammatory responses and pulmonary dysfunction in COPD mouse models. A cytokine protein array revealed that the expression of retinol binding protein 4 (RBP4) was down-regulated by IL-17A, and exogenous RBP4-recombinant protein resulted in a decrease in the severity of P. aeruginosa-induced airway dysfunction. Concurrent application of IL-17A-neutralizing antibody and ciprofloxacin attenuated airway inflammation and ventilation after inoculation of P. aeruginosa in COPD mouse models. Our results revealed that IL-17 plays a detrimental role in the pathogenesis of P. aeruginosa airway infection during acute exacerbations of COPD. Targeting IL-17A is a potential therapeutic strategy in controlling the outcomes of P. aeruginosa infection in COPD patients.

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