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.

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.

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.

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 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 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.

The innate immune system

2020 ◽  
pp. 307-314
Author(s):  
Paul Bowness
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Innate Immune System ◽  
Cell Types ◽  
Innate Immune ◽  
Microbial Pathogens ◽  
Innate Immune Responses ◽  
Adaptive Immune ◽  
System P ◽  
Different Cell Types

The innate immune system comprises evolutionarily ancient mechanisms that mediate first-line responses against microbial pathogens, and are also important in priming and execution of adaptive immune responses, and in defence against tumours. These responses, which recognize microbial non-self, damaged self, and absent self, are characterized by rapidity of action and they involve various different cell types, cell-associated receptors, and soluble factors. Previously thought to lack plasticity or memory, certain innate immune responses have recently been shown to be capable of ‘learning’ or ‘training’. Most cells of the innate immune system are derived from the myeloid precursors in the bone marrow. These include monocytes and their derivatives—macrophages and dendritic cells, blood granulocytes (neutrophils, basophils, and eosinophils), and tissue mast cells.

scholarly journals A30 DIFFERENCES BETWEEN HUMAN AND MOUSE INTESTINAL EPITHELIAL CELLS IN THEIR INNATE IMMUNE RESPONSES TO BACTERIAL AND HOST STIMULI.

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 2-3
Author(s):  
J M Allaire ◽  
A Poon ◽  
S M Crowley ◽  
X Han ◽  
M Stahl ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
Intestinal Epithelial Cells ◽  
Innate Immune ◽  
Negative Regulator ◽  
Intestinal Epithelial ◽  
Innate Immune Responses ◽  
Transformed Cell Lines ◽  
First Time

Abstract Background Intestinal epithelial cells (IEC) reside in close contact with the gut microbiota. It is thus important that IEC are hypo-responsive to bacterial products to prevent maladaptive inflammatory responses in the gut, such as those seen in Inflammatory bowel diseases (IBD). This suppression of innate immune signaling in IEC is in part due to their strong expression of Single Ig IL1 related receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and toll-like receptor (TLR) signaling. IL37, a newly recognized anti-inflammatory cytokine has been shown to strongly inhibit innate signaling in cells by binding to, and signaling through SIGIRR, leading to suppression of various forms of inflammation in mice. Few studies have looked at the function of IL-37/SIGIRR in IEC and their potential use to balance inflammatory responses. Notably, while many groups have studied IEC immune response in vitro, using transformed IEC lines, our focus is on primary-derived IEC which more accurately reflect in vivo responses. Aims To characterize IEC intrinsic and species-specific immune responses elicited by bacteria and host products as well as the role of IL37/SIGIRR in regulating this innate signaling. Methods We used organoid to study the innate immune responses of primary IEC derived from human or mouse colon (colonoids). After stimulation with inflammatory stimuli (IL1β, FliC and LPS), qPCR, ELISA, Milliplex Multiplex Assay and Western blot were used to determine modification in signalling pathway and cytokine/chemokine secretion. Results Using colonoids derived from healthy donors, we demonstrated that unlike transformed cell lines or mouse IEC, human IEC respond only to the bacterial product FliC, and not to LPS or IL1β. We further characterized human colonoid innate immune responses and despite significant inter-individual variability upon FliC stimulation, all organoids released several chemokines (IL8, CXCL1, CXCL2, CCL2 and CCL20). We showed for the first time that IL37 attenuated these innate immune responses through inhibition of intracellular signaling pathways (p38 and NFkB). Using colonoids derived from wildtype and Sigirr deficient mice, we found that mice IEC were responsive to IL1b and FliC and that the suppressive effects of IL37 were Sigirr dependent. Conclusions Our results show that human IEC show variability among individuals in the magnitude of their innate immune responses, and these responses differ from those obtained from transformed cells and primary mouse IEC. For the first time, we show that IL37 suppresses IEC innate immune responses, through its ability to signal through Sigirr. Further investigations will assess the ability of IL37 to control inflammation of IEC derived from IBD patients, as a potential therapeutic to promote gut health. Funding Agencies CAG, CIHRMSFHR

scholarly journals Multi-omics approach to COVID-19: a domain-based literature review

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Chiara Montaldo ◽  
Francesco Messina ◽  
Isabella Abbate ◽  
Manuela Antonioli ◽  
Veronica Bordoni ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Integrated Approach ◽  
Cell Types ◽  
Innate Immune ◽  
Domain Model ◽  
Molecular Signature ◽  
Omics Data ◽  
Innate Immune Responses ◽  
Expert Working Group ◽  
Different Levels

Abstract Background Omics data, driven by rapid advances in laboratory techniques, have been generated very quickly during the COVID-19 pandemic. Our aim is to use omics data to highlight the involvement of specific pathways, as well as that of cell types and organs, in the pathophysiology of COVID-19, and to highlight their links with clinical phenotypes of SARS-CoV-2 infection. Methods The analysis was based on the domain model, where for domain it is intended a conceptual repository, useful to summarize multiple biological pathways involved at different levels. The relevant domains considered in the analysis were: virus, pathways and phenotypes. An interdisciplinary expert working group was defined for each domain, to carry out an independent literature scoping review. Results The analysis revealed that dysregulated pathways of innate immune responses, (i.e., complement activation, inflammatory responses, neutrophil activation and degranulation, platelet degranulation) can affect COVID-19 progression and outcomes. These results are consistent with several clinical studies. Conclusions Multi-omics approach may help to further investigate unknown aspects of the disease. However, the disease mechanisms are too complex to be explained by a single molecular signature and it is necessary to consider an integrated approach to identify hallmarks of severity.

scholarly journals pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production

2021 ◽  
Vol 17 (7) ◽  
pp. e1009733
Author(s):  
Jiangnan Li ◽  
Jie Song ◽  
Li Kang ◽  
Li Huang ◽  
Shijun Zhou ◽  
...  
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
African Swine Fever Virus ◽  
African Swine Fever ◽  
Innate Immune ◽  
Fever Virus ◽  
Type I ◽  
Type I Ifn ◽  
Innate Immune Responses

Inflammatory factors and type I interferons (IFNs) are key components of host antiviral innate immune responses, which can be released from the pathogen-infected macrophages. African swine fever virus (ASFV) has developed various strategies to evade host antiviral innate immune responses, including alteration of inflammatory responses and IFNs production. However, the molecular mechanism underlying inhibition of inflammatory responses and IFNs production by ASFV-encoded proteins has not been fully understood. Here we report that ASFV infection only induced low levels of IL-1β and type I IFNs in porcine alveolar macrophages (PAMs), even in the presence of strong inducers such as LPS and poly(dA:dT). Through further exploration, we found that several members of the multigene family 360 (MGF360) and MGF505 strongly inhibited IL-1β maturation and IFN-β promoter activation. Among them, pMGF505-7R had the strongest inhibitory effect. To verify the function of pMGF505-7R in vivo, a recombinant ASFV with deletion of the MGF505-7R gene (ASFV-Δ7R) was constructed and assessed. As we expected, ASFV-Δ7R infection induced higher levels of IL-1β and IFN-β compared with its parental ASFV HLJ/18 strain. ASFV infection-induced IL-1β production was then found to be dependent on TLRs/NF-κB signaling pathway and NLRP3 inflammasome. Furthermore, we demonstrated that pMGF505-7R interacted with IKKα in the IKK complex to inhibit NF-κB activation and bound to NLRP3 to inhibit inflammasome formation, leading to decreased IL-1β production. Moreover, we found that pMGF505-7R interacted with and inhibited the nuclear translocation of IRF3 to block type I IFN production. Importantly, the virulence of ASFV-Δ7R is reduced in piglets compared with its parental ASFV HLJ/18 strain, which may due to induction of higher IL-1β and type I IFN production in vivo. Our findings provide a new clue to understand the functions of ASFV-encoded pMGF505-7R and its role in viral infection-induced pathogenesis, which might help design antiviral agents or live attenuated vaccines to control ASF.

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