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 Modulation of Innate Immune Responses by the Influenza A NS1 and PA-X Proteins

Viruses ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 708 ◽  
Author(s):  
Aitor Nogales ◽  
Luis Martinez-Sobrido ◽  
David Topham ◽  
Marta DeDiego
Keyword(s):  
Immune Responses ◽  
Influenza A ◽  
Defense Mechanisms ◽  
Synergistic Effects ◽  
Viral Proteins ◽  
Economic Problem ◽  
Innate Immune ◽  
Host Protein ◽  
Innate Immune Responses ◽  
Influenza A Viruses

Influenza A viruses (IAV) can infect a broad range of animal hosts, including humans. In humans, IAV causes seasonal annual epidemics and occasional pandemics, representing a serious public health and economic problem, which is most effectively prevented through vaccination. The defense mechanisms that the host innate immune system provides restrict IAV replication and infection. Consequently, to successfully replicate in interferon (IFN)-competent systems, IAV has to counteract host antiviral activities, mainly the production of IFN and the activities of IFN-induced host proteins that inhibit virus replication. The IAV multifunctional proteins PA-X and NS1 are virulence factors that modulate the innate immune response and virus pathogenicity. Notably, these two viral proteins have synergistic effects in the inhibition of host protein synthesis in infected cells, although using different mechanisms of action. Moreover, the control of innate immune responses by the IAV NS1 and PA-X proteins is subject to a balance that can determine virus pathogenesis and fitness, and recent evidence shows co-evolution of these proteins in seasonal viruses, indicating that they should be monitored for enhanced virulence. Importantly, inhibition of host gene expression by the influenza NS1 and/or PA-X proteins could be explored to develop improved live-attenuated influenza vaccines (LAIV) by modulating the ability of the virus to counteract antiviral host responses. Likewise, both viral proteins represent a reasonable target for the development of new antivirals for the control of IAV infections. In this review, we summarize the role of IAV NS1 and PA-X in controlling the antiviral response during viral infection.

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 Toll-Like Receptor-Triggered Calcium Mobilization Protects Mice against Bacterial Infection through Extracellular ATP Release

2014 ◽  
Vol 82 (12) ◽  
pp. 5076-5085 ◽  
Author(s):  
Hua Ren ◽  
Yunfei Teng ◽  
Binghe Tan ◽  
Xiaoyu Zhang ◽  
Wei Jiang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Pyridoxal Phosphate ◽  
Atp Release ◽  
Extracellular Atp ◽  
Calcium Mobilization ◽  
Innate Immune ◽  
Disulfonic Acid ◽  
Dependent Manner ◽  
Innate Immune Responses ◽  
Toll Like Receptor

ABSTRACTExtracellular ATP (eATP), released as a “danger signal” by injured or stressed cells, plays an important role in the regulation of immune responses, but the relationship between ATP release and innate immune responses is still uncertain. In this study, we demonstrated that ATP was released through Toll-like receptor (TLR)-associated signaling in bothEscherichia coli-infected mice and lipopolysaccharide (LPS)- or Pam3CSK4-treated macrophages. This ATP release could be blocked completely only byN-ethylmaleimide (NEM), not by carbenoxolone (CBX), flufenamic acid (FFA), or probenecid, suggesting the key role of exocytosis in this process. Furthermore, LPS-induced ATP release could also be reduced dramatically through suppressing calcium mobilization by use of U73122, caffeine, and thapsigargin (TG). In addition, the secretion of interleukin-1β (IL-1β) and CCL-2 was enhanced significantly by ATP, in a time- and dose-dependent manner. Meanwhile, macrophage-mediated phagocytosis of bacteria was also promoted significantly by ATP stimulation. Furthermore, extracellular ATP reduced the number of invading bacteria and protected mice from peritonitis by activating purinergic receptors. Mechanistically, phosphorylation of AKT and ERK was overtly increased by ATP in antibacterial immune responses. Accordingly, if we blocked the P2X- and P2Y-associated signaling pathway by using suramin and pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid), tetrasodium salt (PPADS), the ATP-enhanced immune response was restrained significantly. Taken together, our findings reveal an internal relationship between danger signals and TLR signaling in innate immune responses, which suggests a potential therapeutic significance of calcium mobilization-mediated ATP release in infectious diseases.

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 Cutting Edge: Roles of Caspase-8 and Caspase-10 in Innate Immune Responses to Double-Stranded RNA

2006 ◽  
Vol 176 (8) ◽  
pp. 4520-4524 ◽  
Author(s):  
Ken Takahashi ◽  
Taro Kawai ◽  
Himanshu Kumar ◽  
Shintaro Sato ◽  
Shin Yonehara ◽  
...  
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Cutting Edge ◽  
Caspase 8 ◽  
Innate Immune Responses ◽  
Double Stranded Rna

scholarly journals Decoding the role of CBLB for innate immune responses regulating systemic dissemination during Non-Tuberculous Mycobacteria infection

2020 ◽  
Author(s):  
Srinivasu Mudalagiriyappa ◽  
Jaishree Sharma ◽  
Hazem F. M. Abdelaal ◽  
Thomas C. Kelly ◽  
Woosuk Choi ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Granulomatous Inflammation ◽  
Innate Immune ◽  
Dependent Manner ◽  
Innate Immune Responses ◽  
Inflammatory Monocytes ◽  
Cell Immunity

AbstractNon-Tuberculous Mycobacteria (NTM) are ubiquitous in nature, present in soil and water, and cause primary leading to disseminated infections in immunocompromised individuals. NTM infections are surging in recent years due to an increase in an immune-suppressed population, medical interventions, and patients with underlying lung diseases. Host regulators of innate immune responses, frontiers for controlling infections and dissemination, are poorly defined during NTM infections. Here, we describe the role of CBLB, an E3-ubiquitin ligase, for innate immune responses and disease progression in a mouse model of NTM infection under compromised T-cell immunity. We found that CBLB thwarted NTM growth and dissemination in a time- and infection route- dependent manner. Mechanistically, we uncovered defects in many innate immune cells in the absence of Cblb, including poor responses of NK cells, inflammatory monocytes, and conventional dendritic cells. Strikingly, Cblb-deficient macrophages were competent to control NTM growth in vitro. Histopathology suggested the lack of early formation of granulomatous inflammation in the absence of CBLB. Collectively, CBLB is essential to mount productive innate immune responses and help prevent the dissemination during an NTM infection under T-cell deficiency.

scholarly journals The Role of Porphyromonas gingivalis Virulence Factors in Periodontitis Immunopathogenesis

2020 ◽  
Vol 23 (1) ◽  
pp. 6-12
Author(s):  
Tienneke Riana Septiwidyati ◽  
Endang Winiati Bachtiar
Keyword(s):  
Immune Responses ◽  
Porphyromonas Gingivalis ◽  
Virulence Factors ◽  
Defense Mechanisms ◽  
Tooth Loss ◽  
Innate Immune ◽  
Not Given ◽  
Innate Immune Responses ◽  
Oral Bacterium

Porphyromonas gingivalis is an anaerobic Gram-negative oral bacterium involved in the pathogenesis of periodontitis. Periodontitis is an infection that is characterized by damage to the supporting tissues of the teeth so that it can cause tooth loss if not given treatment. P. gingivalis locally can invade periodontal tissue and avoid host defense mechanisms. This bacterium has virulence factors which can cause deregulation of innate immune responses and inflammation in the host. The role of P. gingivalis virulence factors such as capsules, fimbriae, lipopolysaccharides, and gingipain in the pathogenesis of periodontitis will be discussed in this paper.

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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