scholarly journals Regulation of Pulmonary and Systemic Bacterial Lipopolysaccharide Responses in Transgenic Mice Expressing Human Elafin

2003 ◽  
Vol 71 (7) ◽  
pp. 3766-3774 ◽  
Author(s):  
J.-M. Sallenave ◽  
G. A. Cunningham ◽  
R. M. James ◽  
G. McLachlan ◽  
C. Haslett
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Bacterial Lipopolysaccharide ◽  
Dual Function ◽  
Innate Immune Responses ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Elastase Inhibitor ◽  
Tnf Α

ABSTRACT The control of lung inflammation is of paramount importance in a variety of acute pathologies, such as pneumonia, the acute respiratory distress syndrome, and sepsis. It is becoming increasingly apparent that local innate immune responses in the lung are negatively influenced by systemic inflammation. This is thought to be due to a local deficit in cytokine responses by alveolar macrophages and neutrophils following systemic bacterial infection and the development of a septic response. Recently, using an adenovirus-based strategy which overexpresses the human elastase inhibitor elafin locally in the lung, we showed that elafin is able to prime lung innate immune responses. In this study, we generated a novel transgenic mouse strain expressing human elafin and studied its response to bacterial lipopolysaccharide (LPS) when the LPS was administered locally in the lungs and systemically. When LPS was delivered to the lungs, we found that mice expressing elafin had lower serum-to-bronchoalveolar lavage ratios of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), macrophage inflammatory protein 2, and monocyte chemoattractant protein 1, than wild-type mice. There was a concomitant increase in inflammatory cell influx, showing that there was potential priming of innate responses in the lungs. When LPS was given systemically, the mice expressing elafin had reduced levels of serum TNF-α compared to the levels in wild-type mice. These results indicate that elafin may have a dual function, promoting up-regulation of local lung innate immunity while simultaneously down-regulating potentially unwanted systemic inflammatory responses in the circulation.

Innate immune responses of human tracheal epithelium toPseudomonas aeruginosaflagellin, TNF-α, and IL-1β

2006 ◽  
Vol 290 (3) ◽  
pp. C678-C690 ◽  
Author(s):  
Jill Tseng ◽  
Jiun Do ◽  
Jonathan H. Widdicombe ◽  
Terry E. Machen
Keyword(s):  
Immune Responses ◽  
Tight Junctions ◽  
Inflammatory Responses ◽  
Cell Types ◽  
Innate Immune ◽  
Apical Surface ◽  
Basal Cells ◽  
Innate Immune Responses ◽  
Tnf Α ◽  
Columnar Cells

We measured innate immune responses by primary human tracheal epithelial (HTE) cells grown as confluent, pseudostratified layers during exposure to inflammatory activators on apical vs. basolateral surfaces. Apical Pseudomonas aeruginosa strain PAK (but not flagellin mutant PAK·fliC), flagellin, and flagellin + PAK·fliC activated NF-κB and IL-8 expression and secretion. In contrast, HTE cells were insensitive to LPS compared to flagellin. Flagellin activated NF-κB in columnar but not basal cells. IL-1β + TNF-α elicited responses similar to those of flagellin. Basolateral flagellin or IL-1β + TNF-α caused 1.5- to 4-fold larger responses, consistent with the fact that NF-κB activation occurred in both columnar and basal cells. MyD88 (toll receptor-associated adapter), IL-1 receptor (IL1R)1, and TNF-α receptor (TNFR)1 were expressed in columnar and basal cells. ZO-1 was localized to tight junctions of columnar cells but not to basal cells. We infer the following. 1) Flagellin is necessary and sufficient to trigger inflammatory responses in columnar cells during accumulation of P. aeruginosa in the airway surface liquid (ASL); columnar cells express toll-like receptor 5 and MyD88, often associated with flagellin-activated cell signaling. 2) IL-1β + TNF-α in the ASL also activate columnar cells, and these cells also express IL1R1 and TNFR1. 3) Apical flagellin, IL-1β, and TNF-α do not activate basal cells because tight junctions between columnar cells prevent access from the apical surface to the basal cells. 4) Exposure of basolateral surfaces to inflammatory activators elicits larger responses because both columnar and basal cells are activated, likely because both cell types express receptors for flagellin, IL-1β, and TNF-α.

Effect of aerobic exercise on innate immune responses and inflammatory mediators in the spinal cord of diabetic rats

2020 ◽  
Vol 16 (4) ◽  
pp. 293-301
Author(s):  
A. Kaki ◽  
M. Nikbakht ◽  
A.H. Habibi ◽  
H.F. Moghadam
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Immune Responses ◽  
Diabetic Neuropathy ◽  
Aerobic Exercise ◽  
Inflammatory Mediators ◽  
Innate Immune ◽  
Moderate Intensity ◽  
Innate Immune Responses ◽  
Tnf Α

Neuronal inflammation is one of the pathophysiological causes of diabetes neuropathic pain. The purpose of this research was to determine the effect of aerobic exercise on innate immune responses and inflammatory mediators in the spinal dorsal horn in rats with diabetic neuropathic pain. 40 eight-week-old male Wistar rats (weight range 220±10.2 g) were randomly divided into four groups of (1) sedentary diabetic neuropathy (SDN), (2) training diabetic neuropathy (TDN), (3) training control (TC), and (4) sedentary control (SC). Diabetes was induced by injection of streptozocin (50 mg/kg). Following confirmation of behavioural tests for diabetes neuropathy, the training groups performed 6 weeks of moderate-intensity aerobic exercise on the treadmill. The expression of Toll like receptor (TLR)4, TLR2, tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-10 genes in L4-L6 spinal cord sensory neurons was measured by Real Time PCR. Two-way ANOVA and Bonferroni’s post hoc tests were used for statistical analysis. After performing aerobic exercise protocol, the TDN compared to the SDN showed a significant decrease in the mean score of pain in the formalin test and a significant increase in the latency in Tail-Flick test was observed. The expression of TLR4, TLR2, TNF-α and IL-1β genes was significantly higher in the SDN than in the SC group (P<0.05). The expression of the above genes in the TDN was significantly lower than the SDN group (P<0.05). Also, the expression level of IL-10 gene was significantly higher in the TDN than the SDN group (P<0.05). Aerobic exercise improved sensitivity of nociceptors to pain-inducing agents in diabetic neuropathy due to inhibition of inflammatory receptors and increased levels of anti-inflammatory agents in the nervous system. Thus, aerobic exercise should be used as a non-pharmacological intervention for diabetic patients to reduce neuropathic pain.

scholarly journals Effects of elevated CO2 levels on lung immune response to organic dust and lipopolysaccaride

2021 ◽  
Author(s):  
David Schneberger ◽  
Upkardeep Singh Pandher ◽  
Brooke Thompson ◽  
Shelley Kirychuk
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Animal Feed ◽  
Weighted Average ◽  
Innate Immune ◽  
Mrna Levels ◽  
Innate Immune Responses ◽  
Organic Dust ◽  
Complex Environments ◽  
Time Weighted Average

Abstract Workplaces with elevated organic dust levels such as animal feed barns also commonly have elevated levels of gasses, such as CO2. Workers exposed to such complex environments often experience respiratory effects that may be due to a combination of respirable factors. We examined the effects of CO2 at the ASHRAE recommended limit (1000 ppm) as well as the EPA 8hr time weighted average limit (5000 ppm) on lung innate immune responses in mice with exposure to inflammatory lipopolysaccharide and organic dust. Mice were nasally instilled with dust extracts or LPS and immediately put into chambers with a constant flow of room air (approx. 430 ppm CO2), 1000 ppm, or 5000 ppm CO2 enriched air. Organic dust exposures tended to show decreased inflammatory responses with 1000 ppm CO2 and increased responses at 5000 ppm CO2. Conversely, LPS with addition of CO2 as low as 1000 ppm tended to inhibit several inflammatory markers. In most cases saline treated animals showed few changes with CO2 exposure, though some changes in mRNA levels were present. This shows that CO2 as low as 1000 ppm CO2 was capable of altering innate immune responses to both LPS and organic dust extracts, but each response was altered in a different fashion.

scholarly journals Inflammation and the Gut-Liver Axis in the Pathophysiology of Cholangiopathies

2018 ◽  
Vol 19 (10) ◽  
pp. 3003 ◽  
Author(s):  
Debora Giordano ◽  
Claudio Pinto ◽  
Luca Maroni ◽  
Antonio Benedetti ◽  
Marco Marzioni
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Enterohepatic Circulation ◽  
Intestinal Barrier ◽  
Cell Types ◽  
Innate Immune ◽  
Primary Biliary Cholangitis ◽  
Innate Immune Responses ◽  
Adaptive Immune Cells ◽  
Bacterial Products

Cholangiocytes, the epithelial cells lining the bile ducts, represent the unique target of a group of progressive diseases known as cholangiopathies whose pathogenesis remain largely unknown. In normal conditions, cholangiocytes are quiescent and participate to the final bile volume and composition. Following exogenous or endogenous stimuli, cholangiocytes undergo extensive modifications of their phenotype. Reactive cholangiocytes actively proliferate and release a set of proinflammatory molecules, which act in autocrine/paracrine manner mediating the cross-talk with other liver cell types and innate and adaptive immune cells. Cholangiocytes themselves activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Gut microbiota has been implicated in the development and progression of the two most common cholangiopathies, i.e., primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), which have distinctive microbiota composition compared to healthy individuals. The impairment of intestinal barrier functions or gut dysbiosis expose cholangiocytes to an increasing amount of microorganisms and may exacerbate inflammatory responses thus leading to fibrotic remodeling of the organ. The present review focuses on the complex interactions between the activation of innate immune responses in reactive cholangiocytes, dysbiosis, and gut permeability to bacterial products in the pathogenesis of PSC and PBC.

Cellular and molecular insights on the regulation of innate immune responses to experimental aspergillosis in chicken and turkey poults

2020 ◽  
Author(s):  
Tobias Vahsen ◽  
Laura Zapata ◽  
Rodrigo Guabiraba ◽  
Elise Melloul ◽  
Nathalie Cordonnier ◽  
...  
Keyword(s):  
Immune Responses ◽  
Aspergillus Fumigatus ◽  
Inflammatory Responses ◽  
Clinical Signs ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Lung Lesions ◽  
Turkey Poults ◽  
Cd8 T Lymphocyte ◽  
Fungal Immunity

Abstract Across the world, many commercial poultry flocks and captive birds are threatened by infection with Aspergillus fumigatus. Susceptibility to aspergillosis varies among birds; among galliform birds specifically, morbidity and mortality rates seem to be greater in turkeys than in chickens. Little is known regarding the features of avian immune responses after inhalation of Aspergillus conidia, and to date, scarce information on inflammatory responses during aspergillosis exists. Thus, in the present study, we aimed to improve our understanding of the interactions between A. fumigatus and economically relevant galliform birds in terms of local innate immune responses. Intra-tracheal aerosolization of A. fumigatus conidia in turkey and chicken poults led to more severe clinical signs and lung lesions in turkeys, but leukocyte recovery from lung lavages was higher in chickens at 1dpi only. Interestingly, only chicken CD8+ T lymphocyte proportions increased after infection. Furthermore, the lungs of infected chickens showed an early upregulation of pro-inflammatory cytokines, including IL-1β, IFN-γ and IL-6, whereas in turkeys, most of these cytokines showed a downregulation or a delayed upregulation. These results confirmed the importance of an early pro-inflammatory response to ensure the development of an appropriate anti-fungal immunity to avoid Aspergillus dissemination in the respiratory tract. In conclusion, we show for the first time that differences in local innate immune responses between chickens and turkeys during aspergillosis may determine the outcome of the disease. Lay Summary Aspergillus fumigatus infection may cause mortality in poultry, depending on species sensitivity. This study confirms the earlier activation of chickens’ pro-inflammatory effectors to control Aspergillus dissemination, whereas turkeys’ immune response enables the exacerbation of lung lesions.

scholarly journals Toll-like Receptor 7 Contributes to Inflammation, Organ Injury, and Mortality in Murine Sepsis

2019 ◽  
Vol 131 (1) ◽  
pp. 105-118 ◽  
Author(s):  
Wenling Jian ◽  
Lili Gu ◽  
Brittney Williams ◽  
Yan Feng ◽  
Wei Chao ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Immune Responses ◽  
Knockout Mice ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Innate Immune ◽  
Organ Injury ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Wild Type

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Sepsis remains a critical illness with high mortality. The authors have recently reported that mouse plasma RNA concentrations are markedly increased during sepsis and closely associated with its severity. Toll-like receptor 7, originally identified as the sensor for single-stranded RNA virus, also mediates host extracellular RNA-induced innate immune responses in vitro and in vivo. Here, the authors hypothesize that innate immune signaling via Toll-like receptor 7 contributes to inflammatory response, organ injury, and mortality during polymicrobial sepsis. Methods Sepsis was created by (1) cecal ligation and puncture or (2) stool slurry peritoneal injection. Wild-type and Toll-like receptor 7 knockout mice, both in C57BL/6J background, were used. The following endpoints were measured: mortality, acute kidney injury biomarkers, plasma and peritoneal cytokines, blood bacterial loading, peritoneal leukocyte counts, and neutrophil phagocytic function. Results The 11-day overall mortality was 81% in wild-type mice and 48% in Toll-like receptor 7 knockout mice after cecal ligation and puncture (N = 27 per group, P = 0.0031). Compared with wild-type septic mice, Toll-like receptor 7 knockout septic mice also had lower sepsis severity, attenuated plasma cytokine storm (wild-type vs. Toll-like receptor 7 knockout, interleukin-6: 43.2 [24.5, 162.7] vs. 4.4 [3.1, 12.0] ng/ml, P = 0.003) and peritoneal inflammation, alleviated acute kidney injury (wild-type vs. Toll-like receptor 7 knockout, neutrophil gelatinase-associated lipocalin: 307 ± 184 vs.139 ± 41-fold, P = 0.0364; kidney injury molecule-1: 40 [16, 49] vs.13 [4, 223]-fold, P = 0.0704), lower bacterial loading, and enhanced leukocyte peritoneal recruitment and phagocytic activities at 24 h. Moreover, stool slurry from wild-type and Toll-like receptor 7 knockout mice resulted in similar level of sepsis severity, peritoneal cytokines, and leukocyte recruitment in wild-type animals after peritoneal injection. Conclusions Toll-like receptor 7 plays an important role in the pathogenesis of polymicrobial sepsis by mediating host innate immune responses and contributes to acute kidney injury and mortality.

scholarly journals Lipopolysaccharide and Tumor Necrosis Factor Alpha Inhibit Interferon Signaling in Hepatocytes by Increasing Ubiquitin-Like Protease 18 (USP18) Expression

2016 ◽  
Vol 90 (12) ◽  
pp. 5549-5560 ◽  
Author(s):  
Sonya A. MacParland ◽  
Xue-Zhong Ma ◽  
Limin Chen ◽  
Ramzi Khattar ◽  
Vera Cherepanov ◽  
...  
Keyword(s):  
Viral Infections ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Innate Immune ◽  
New Paradigm ◽  
Hepatic Ischemia ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Inflammatory Stimuli

ABSTRACTInflammation may be maladaptive to the control of viral infection when it impairs interferon (IFN) responses, enhancing viral replication and spread. Dysregulated immunity as a result of inappropriate innate inflammatory responses is a hallmark of chronic viral infections such as, hepatitis B virus and hepatitis C virus (HCV). Previous studies from our laboratory have shown that expression of an IFN-stimulated gene (ISG), ubiquitin-like protease (USP)18 is upregulated in chronic HCV infection, leading to impaired hepatocyte responses to IFN-α. We examined the ability of inflammatory stimuli, including tumor necrosis factor alpha (TNF-α), lipopolysaccharide (LPS), interleukin-6 (IL-6) and IL-10 to upregulate hepatocyte USP18 expression and blunt the IFN-α response. Human hepatoma cells and primary murine hepatocytes were treated with TNF-α/LPS/IL-6/IL-10 and USP18, phosphorylated (p)-STAT1 and myxovirus (influenza virus) resistance 1 (Mx1) expression was determined. Treatment of Huh7.5 cells and primary murine hepatocytes with LPS and TNF-α, but not IL-6 or IL-10, led to upregulated USP18 expression and induced an IFN-α refractory state, which was reversed by USP18 knockdown. Liver inflammation was induced in vivo using a murine model of hepatic ischemia/reperfusion injury. Hepatic ischemia/reperfusion injury led to an induction of USP18 expression in liver tissue and promotion of lymphocytic choriomeningitis replication. These data demonstrate that certain inflammatory stimuli (TNF-α and LPS) but not others (IL-6 and IL-10) target USP18 expression and thus inhibit IFN signaling. These findings represent a new paradigm for how inflammation alters hepatic innate immune responses, with USP18 representing a potential target for intervention in various inflammatory states.IMPORTANCEInflammation may prevent the control of viral infection when it impairs the innate immune response, enhancing viral replication and spread. Blunted immunity as a result of inappropriate innate inflammatory responses is a common characteristic of chronic viral infections. Previous studies have shown that expression of certain interferon-stimulated genes is upregulated in chronic HCV infection, leading to impaired hepatocyte responses. In this study, we show that multiple inflammatory stimuli can modulate interferon stimulated gene expression and thus inhibit hepatocyte interferon signaling via USP18 induction. These findings represent a new paradigm for how inflammation alters hepatic innate immune responses, with the induction of USP18 representing a potential target for intervention in various inflammatory states.

scholarly journals Caspase-8 is activated by cathepsin D initiating neutrophil apoptosis during the resolution of inflammation

2008 ◽  
Vol 205 (3) ◽  
pp. 685-698 ◽  
Author(s):  
Sébastien Conus ◽  
Remo Perozzo ◽  
Thomas Reinheckel ◽  
Christoph Peters ◽  
Leonardo Scapozza ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cathepsin D ◽  
Defense Mechanisms ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Caspase 8 ◽  
Neutrophil Apoptosis ◽  
Dependent Manner ◽  
Innate Immune Responses ◽  
Inflammatory Conditions

In the resolution of inflammatory responses, neutrophils rapidly undergo apoptosis. We describe a new proapoptotic pathway in which cathepsin D directly activates caspase-8. Cathepsin D is released from azurophilic granules in neutrophils in a caspase-independent but reactive oxygen species–dependent manner. Under inflammatory conditions, the translocation of cathepsin D in the cytosol is blocked. Pharmacological or genetic inhibition of cathepsin D resulted in delayed caspase activation and reduced neutrophil apoptosis. Cathepsin D deficiency or lack of its translocation in the cytosol prolongs innate immune responses in experimental bacterial infection and in septic shock. Thus, we identified a new function of azurophilic granules that is in addition to their role in bacterial defense mechanisms: to regulate the life span of neutrophils and, therefore, the duration of innate immune responses through the release of cathepsin D.

scholarly journals Toll-Like Receptor-Initiated Testicular Innate Immune Responses in Mouse Leydig Cells

Endocrinology ◽  
2011 ◽  
Vol 152 (7) ◽  
pp. 2827-2836 ◽  
Author(s):  
Tao Shang ◽  
Xiaoyan Zhang ◽  
Tao Wang ◽  
Bing Sun ◽  
Tingting Deng ◽  
...  
Keyword(s):  
Immune Responses ◽  
Tyrosine Kinases ◽  
Leydig Cells ◽  
Innate Immune ◽  
Inflammatory Factors ◽  
Innate Immune Responses ◽  
Polyinosinic:Polycytidylic Acid ◽  
Tnf Α ◽  
Microbial Infections ◽  
Local Cell

The testis is an immunoprivileged site, where the local cell-initiated testicular innate immune responses play a crucial role in defense against microbial infections. Mechanisms modulating the testicular cell-built defense system remain to be clarified. In this article, we demonstrate that Leydig cells, a major cell population in the testicular interstitium, initiate innate immunity through the activation of Toll-like receptors (TLRs). Several TLRs are expressed in mouse Leydig cells; among these, TLR3 and TLR4 are expressed at relatively high levels compared with other TLR members. Both TLR3 and TLR4 can be activated by their agonists (polyinosinic:polycytidylic acid and lipopolysaccharide) in Leydig cells and subsequently induce the production of inflammatory factors, such as IL-1β, IL-6, TNF-α, and type 1 interferons (IFN) (IFN-α and IFN-β). Notably, the activation of TLR3 and TLR4 suppresses steroidogenesis by Leydig cells. Further, we provide evidence that Axl and Mer receptor tyrosine kinases are expressed in Leydig cells and regulate TLR-mediated innate immune responses negatively. Data presented here describe a novel function of Leydig cells in eliciting testicular innate immune responses that should contribute to the protection of the testis from microbial infections.

scholarly journals How the Innate Immune DNA Sensing cGAS–STING Pathway Is Involved in Autophagy

2021 ◽  
Vol 22 (24) ◽  
pp. 13232
Author(s):  
Wanglong Zheng ◽  
Nengwen Xia ◽  
Jiajia Zhang ◽  
Nanhua Chen ◽  
François Meurens ◽  
...  
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Complex Interaction ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Innate Immune Responses ◽  
Homeostatic Process ◽  
Sting Pathway ◽  
Dna Complex

The cGAS–STING pathway is a key component of the innate immune system and exerts crucial roles in the detection of cytosolic DNA and invading pathogens. Accumulating evidence suggests that the intrinsic cGAS–STING pathway not only facilitates the production of type I interferons (IFN-I) and inflammatory responses but also triggers autophagy. Autophagy is a homeostatic process that exerts multiple effects on innate immunity. However, systematic evidence linking the cGAS–STING pathway and autophagy is still lacking. Therefore, one goal of this review is to summarize the known mechanisms of autophagy induced by the cGAS–STING pathway and their consequences. The cGAS–STING pathway can trigger canonical autophagy through liquid-phase separation of the cGAS–DNA complex, interaction of cGAS and Beclin-1, and STING-triggered ER stress–mTOR signaling. Furthermore, both cGAS and STING can induce non-canonical autophagy via LC3-interacting regions and binding with LC3. Subsequently, autophagy induced by the cGAS–STING pathway plays crucial roles in balancing innate immune responses, maintaining intracellular environmental homeostasis, alleviating liver injury, and limiting tumor growth and transformation.

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