scholarly journals Wound-induced Ca2+ wave propagates through a simple release and diffusion mechanism

2017 ◽  
Vol 28 (11) ◽  
pp. 1457-1466 ◽  
Author(s):  
L. Naomi Handly ◽  
Roy Wollman
Keyword(s):  
Diffusion Model ◽  
Tissue Damage ◽  
Atp Hydrolysis ◽  
Inflammatory Responses ◽  
Diffusion Mechanism ◽  
Fast Activation ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
And Diffusion ◽  
Source And Sink

Damage-associated molecular patterns (DAMPs) are critical mediators of information concerning tissue damage from damaged cells to neighboring healthy cells. ATP acts as an effective DAMP when released into extracellular space from damaged cells. Extracellular ATP receptors monitor tissue damage and activate a Ca2+ wave in the surrounding healthy cells. How the Ca2+ wave propagates through cells after a wound is unclear. Ca2+ wave activation can occur extracellularly via external receptors or intracellularly through GAP junctions. Three potential mechanisms to propagate the Ca2+ wave are source and sink, amplifying wave, and release and diffusion. Both source and sink and amplifying wave regulate ATP levels using hydrolysis or secretion, respectively, whereas release and diffusion relies on dilution. Here we systematically test these hypotheses using a microfluidics assay to mechanically wound an epithelial monolayer in combination with direct manipulation of ATP hydrolysis and release. We show that a release and diffusion model sufficiently explains Ca2+-wave propagation after an epithelial wound. A release and diffusion model combines the benefits of fast activation at short length scales with a self-limiting response to prevent unnecessary inflammatory responses harmful to the organism.

scholarly journals Wound induced Ca2+ wave propagates through a simple Release and Diffusion mechanism

2016 ◽  
Author(s):  
Naomi Handly ◽  
Roy Wollman
Keyword(s):  
Diffusion Model ◽  
Tissue Damage ◽  
Atp Hydrolysis ◽  
Inflammatory Responses ◽  
Diffusion Mechanism ◽  
Fast Activation ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
And Diffusion ◽  
Source And Sink

Damage associated molecular patterns (DAMPs) are critical mediators of information concerning tissue damage from damaged cells to neighboring healthy cells. Adenosine triphosphate (ATP) acts as an effective DAMP when released into extracellular space from damaged cells. Extracellular ATP receptors monitor tissue damage and activate a Ca2+ wave in the surrounding healthy cells. How the Ca2+ wave propagates through cells following a wound is unclear. Ca2+ wave activation can occur extracellularly via external receptors or intracellularly through GAP junctions. Three potential mechanisms to propagate the Ca2+ wave are: Source and Sink, Amplifying Wave, and Release and Diffusion. Both Source and Sink and Amplifying Wave regulate ATP levels using hydrolysis or secretion, respectively, while Release and Diffusion relies on dilution. Here we systematically test these hypotheses using a microfluidics assay to mechanically wound an epithelial monolayer in combination with direct manipulation of ATP hydrolysis and release. We show that a Release and Diffusion model sufficiently explains Ca2+ wave propagation following an epithelial wound. A Release and Diffusion model combines the benefits of fast activation at length-scales of ~1-5 cell diameters with a self-limiting response to prevent unnecessary inflammatory responses harmful to the organism.

scholarly journals DAMPening Inflammation by Modulating TLR Signalling

2010 ◽  
Vol 2010 ◽  
pp. 1-21 ◽  
Author(s):  
A. M. Piccinini ◽  
K. S. Midwood
Keyword(s):  
Immune System ◽  
Tissue Damage ◽  
Tissue Repair ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Feedback Loops ◽  
Inflammatory Gene Expression ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Tlr Signalling

Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.

scholarly journals Untangling Local Pro-Inflammatory, Reparative, and Regulatory Damage-Associated Molecular-Patterns (DAMPs) Pathways to Improve Transplant Outcomes

2021 ◽  
Vol 12 ◽  
Author(s):  
Gaelen K. Dwyer ◽  
Hēth R. Turnquist
Keyword(s):  
Organ Transplantation ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Solid Organ Transplantation ◽  
Experimental Studies ◽  
Surgical Trauma ◽  
Solid Organ ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Detrimental inflammatory responses after solid organ transplantation are initiated when immune cells sense pathogen-associated molecular patterns (PAMPs) and certain damage-associated molecular patterns (DAMPs) released or exposed during transplant-associated processes, such as ischemia/reperfusion injury (IRI), surgical trauma, and recipient conditioning. These inflammatory responses initiate and propagate anti-alloantigen (AlloAg) responses and targeting DAMPs and PAMPs, or the signaling cascades they activate, reduce alloimmunity, and contribute to improved outcomes after allogeneic solid organ transplantation in experimental studies. However, DAMPs have also been implicated in initiating essential anti-inflammatory and reparative functions of specific immune cells, particularly Treg and macrophages. Interestingly, DAMP signaling is also involved in local and systemic homeostasis. Herein, we describe the emerging literature defining how poor outcomes after transplantation may result, not from just an over-abundance of DAMP-driven inflammation, but instead an inadequate presence of a subset of DAMPs or related molecules needed to repair tissue successfully or re-establish tissue homeostasis. Adverse outcomes may also arise when these homeostatic or reparative signals become dysregulated or hijacked by alloreactive immune cells in transplant niches. A complete understanding of the critical pathways controlling tissue repair and homeostasis, and how alloimmune responses or transplant-related processes disrupt these will lead to new immunotherapeutics that can prevent or reverse the tissue pathology leading to lost grafts due to chronic rejection.

A Resource Recommendation Method Based on User Taste Diffusion Model in Folksonomies

2012 ◽  
Vol 3 (1) ◽  
pp. 18-30 ◽  
Author(s):  
Jiangning Wu ◽  
Yunfei Shi ◽  
Chonghui Guo
Keyword(s):  
Diffusion Model ◽  
Diffusion Mechanism ◽  
Personalized Recommendation ◽  
Collaborative Tagging ◽  
Relation Model ◽  
Sparsity Problem ◽  
The Given ◽  
And Diffusion ◽  
Tagging System ◽  
The Web

Collaborative tagging has been very popular with the development of the Web 2.0, which helps users manage, share and utilize resources effectively. For various kinds of resources, the way to recommend appropriate resources to right users is the key problem in tagging system. This paper proposes a user taste diffusion model based on the tripartite hypergraph to deal with the tri-relation of user-resource-tag in folksonomies and the data sparsity problem in personalized recommendation. Through the defined tri-relation model and diffusion probability matrix, the user’s taste is diffused from itself to other users, resources and tags. When diffusion stops, the candidate resources can be identified then be ranked according to the taste values. As a result the top resources that have not been collected by the given user are selected as the final recommendations. Benefiting from the introduction of iterative diffusion mechanism, the recommendation results not only cover the resources collected by the given user’s direct neighbors but also cover the ones which are collected by his/her extended neighbors. Experimental results show that our method performs better in terms of precision and recall than other recommendation methods.

scholarly journals Cranberry Proanthocyanidins Neutralize the Effects of Aggregatibacter actinomycetemcomitans Leukotoxin

Toxins ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 662 ◽  
Author(s):  
Amel Ben Lagha ◽  
Amy Howell ◽  
Daniel Grenier
Keyword(s):  
Gene Expression ◽  
Inflammatory Responses ◽  
Disease Process ◽  
Aggregatibacter Actinomycetemcomitans ◽  
Aggressive Periodontitis ◽  
Cytotoxic Activities ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Aggregatibacter actinomycetemcomitans is a Gram-negative bacterium that has been strongly associated with localized aggressive periodontitis. The capacity of A. actinomycetemcomitans to produce a leukotoxin (LtxA) that activates pyroptosis in macrophages and induces the release of endogenous danger signals is thought to play a key role in the disease process. The aim of the present study was to investigate the effects of cranberry proanthocyanidins (PACs) on gene expression and cytotoxic activities of LtxA. We showed that cranberry PACs dose-dependently attenuate the expression of genes making up the leukotoxin operon, including ltxB and ltxC, in the two strains of A. actinomycetemcomitans tested. Cranberry PACs (≥62.5 µg/mL) protected macrophages against the cytotoxic effect of purified LtxA. Moreover, cranberry PACs reduced caspase-1 activation in LtxA-treated macrophages and consequently decreased the release of both IL-1β and IL-18, which are known as damage-associated molecular patterns (DAMPs) and contribute to the progression of periodontitis by increasing cell migration and osteoclastogenesis. In addition, cranberry PACs reduced the expression of genes encoding the P2X7 receptor and NALP3 (NACHT, LRR and PYD domains-containing protein 3), which play key roles in pore formation and cell death. Lastly, cranberry PACs blocked the binding of LtxA to macrophages and consequently reduced the LtxA-mediated cytotoxicity. In summary, the present study showed that cranberry PACs reduced LtxA gene expression in A. actinomycetemcomitans and neutralized the cytolytic and pro-inflammatory responses of human macrophages treated with LtxA. Given these properties, cranberry PACs may represent promising molecules for prevention and treatment of the aggressive form of periodontitis caused by A. actinomycetemcomitans.

scholarly journals Tissue damage drives co-localization of NF-κB, Smad3, and Nrf2 to direct Rev-erb sensitive wound repair in mouse macrophages

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Dawn Z Eichenfield ◽  
Ty Dale Troutman ◽  
Verena M Link ◽  
Michael T Lam ◽  
Han Cho ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Tissue Damage ◽  
Wound Repair ◽  
Macrophage Polarization ◽  
Expression Of Genes ◽  
Mouse Macrophages ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Although macrophages can be polarized to distinct phenotypes in vitro with individual ligands, in vivo they encounter multiple signals that control their varied functions in homeostasis, immunity, and disease. Here, we identify roles of Rev-erb nuclear receptors in regulating responses of mouse macrophages to complex tissue damage signals and wound repair. Rather than reinforcing a specific program of macrophage polarization, Rev-erbs repress subsets of genes that are activated by TLR ligands, IL4, TGFβ, and damage-associated molecular patterns (DAMPS). Unexpectedly, a complex damage signal promotes co-localization of NF-κB, Smad3, and Nrf2 at Rev-erb-sensitive enhancers and drives expression of genes characteristic of multiple polarization states in the same cells. Rev-erb-sensitive enhancers thereby integrate multiple damage-activated signaling pathways to promote a wound repair phenotype.

scholarly journals Mechanistic Roles of Matrilin-2 and Klotho in Modulating the Inflammatory Activity of Human Aortic Valve Cells

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 385
Author(s):  
Erlinda The ◽  
Qingzhou Yao ◽  
Peijian Zhang ◽  
Yufeng Zhai ◽  
Lihua Ao ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Inflammatory Responses ◽  
Chronic Inflammatory Disease ◽  
Inflammatory Activity ◽  
Protein Kinase R ◽  
Calcific Aortic Valve Disease ◽  
Inflammatory Mediator Production ◽  
Human Aortic Valve ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Background: Calcific aortic valve disease (CAVD) is a chronic inflammatory disease. Soluble extracellular matrix (ECM) proteins can act as damage-associated molecular patterns and may induce valvular inflammation. Matrilin-2 is an ECM protein and has been found to elevate the pro-osteogenic activity in human aortic valve interstitial cells (AVICs). Klotho, an anti-aging protein, appears to have anti-inflammatory properties. The effect of matrilin-2 and Klotho on AVIC inflammatory responses remains unclear. Methods and Results: Isolated human AVICs were exposed to matrilin-2. Soluble matrilin-2 induced the production of ICAM-1, MCP-1, and IL-6. It also induced protein kinase R (PKR) activation via Toll-like receptor (TLR) 2 and 4. Pretreatment with PKR inhibitors inhibited NF-κB activation and inflammatory mediator production induced by matrilin-2. Further, recombinant Klotho suppressed PKR and NF-κB activation and markedly reduced the production of inflammatory mediators in human AVICs exposed to matrilin-2. Conclusions: This study revealed that soluble matrilin-2 upregulates AVIC inflammatory activity via activation of the TLR-PKR-NF-κB pathway and that Klotho is potent to suppress AVIC inflammatory responses to a soluble ECM protein through inhibiting PKR. These novel findings indicate that soluble matrilin-2 may accelerate the progression of CAVD by inducing valvular inflammation and that Klotho has the potential to suppress valvular inflammation.

scholarly journals Aggregated and hyperstable damage-associated molecular patterns are released during ER stress to modulate immune function

2019 ◽  
Author(s):  
Alexander Andersohn ◽  
M. Iveth Garcia ◽  
Ying Fan ◽  
Max C. Thompson ◽  
Askar M. Akimzhanov ◽  
...  
Keyword(s):  
Er Stress ◽  
Systemic Inflammation ◽  
Protein Misfolding ◽  
Inflammatory Responses ◽  
Traumatic Injury ◽  
Adverse Outcomes ◽  
The Unfolded Protein Response ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

AbstractChronic ER stress occurs when protein misfolding in the ER lumen remains unresolved despite activation of the unfolded protein response. We have shown that traumatic injury such as a severe burn leads to chronic ER stressin vivoleading to systemic inflammation which can last for more than a year. The mechanisms linking chronic ER stress to systemic inflammatory responses is not clear. Here we show that induction of chronic ER stress leads to the release of known and novel damage-associated molecular patterns (DAMPs). The secreted DAMPs are aggregated and markedly protease resistant. ER stress-derived DAMPs activate dendritic cells which are then capable of polarizing naïve T cells. Our findings indicate that induction of chronic ER stress may lead to the release of hyperstable DAMPs into the circulation resulting in persistent systemic inflammation and adverse outcomes.

Inflammatory outcomes of apoptosis, necrosis and necroptosis

2014 ◽  
Vol 395 (10) ◽  
pp. 1163-1171 ◽  
Author(s):  
Pavel Davidovich ◽  
Conor J. Kearney ◽  
Seamus J. Martin
Keyword(s):  
Cell Death ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Necrotic Cell Death ◽  
Caspase Activation ◽  
Microbial Infection ◽  
Necrotic Cell ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Pro Inflammatory Cytokines

Abstract Microbial infection and tissue injury are well established as the two major drivers of inflammation. However, although it is widely accepted that necrotic cell death can trigger or potentiate inflammation, precisely how this is achieved still remains relatively obscure. Certain molecules, which have been dubbed ‘damage-associated molecular patterns’ (DAMPs) or alarmins, are thought to promote inflammation upon release from necrotic cells. However, the precise nature and relative potency of DAMPs, compared to conventional pro-inflammatory cytokines or pathogen-associated molecular patterns (PAMPs), remains unclear. How different modes of cell death impact on the immune system also requires further clarification. Apoptosis has long been regarded as a non-inflammatory or even anti-inflammatory mode of cell death, but recent studies suggest that this is not always the case. Necroptosis is a programmed form of necrosis that is engaged under certain conditions when caspase activation is blocked. Necroptosis is also regarded as a highly pro-inflammatory mode of cell death but there has been little explicit examination of this issue. Here we discuss the inflammatory implications of necrosis, necroptosis and apoptosis and some of the unresolved questions concerning how dead cells influence inflammatory responses.

scholarly journals Inflammasomes in Teleosts: Structures and Mechanisms That Induce Pyroptosis during Bacterial Infection

2021 ◽  
Vol 22 (9) ◽  
pp. 4389
Author(s):  
Natsuki Morimoto ◽  
Tomoya Kono ◽  
Masahiro Sakai ◽  
Jun-ichi Hikima
Keyword(s):  
Inflammatory Responses ◽  
Current Knowledge ◽  
Adaptor Protein ◽  
Protective Role ◽  
Inflammasome Activation ◽  
Multiple Protein ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Oligomerization Domain

Pattern recognition receptors (PRRs) play a crucial role in inducing inflammatory responses; they recognize pathogen-associated molecular patterns, damage-associated molecular patterns, and environmental factors. Nucleotide-binding oligomerization domain-leucine-rich repeat-containing receptors (NLRs) are part of the PRR family; they form a large multiple-protein complex called the inflammasome in the cytosol. In mammals, the inflammasome consists of an NLR, used as a sensor molecule, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) as an adaptor protein, and pro-caspase1 (Casp1). Inflammasome activation induces Casp1 activation, promoting the maturation of proinflammatory cytokines, such as interleukin (IL)-1β and IL-18, and the induction of inflammatory cell death called pyroptosis via gasdermin D cleavage in mammals. Inflammasome activation and pyroptosis in mammals play important roles in protecting the host from pathogen infection. Recently, numerous inflammasome-related genes in teleosts have been identified, and their conservation and/or differentiation between their expression in mammals and teleosts have also been elucidated. In this review, we summarize the current knowledge of the molecular structure and machinery of the inflammasomes and the ASC-spec to induce pyroptosis; moreover, we explore the protective role of the inflammasome against pathogenic infection in teleosts.

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