scholarly journals Characterizing the Extent of Cell Death in Innate Immune Mediated Colitis

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Justin R. Hendrix ◽  
Anne-Marie Overstreet ◽  
Antonia Boger-May ◽  
David Boone
Keyword(s):  
Innate Immunity ◽  
Cell Death ◽  
Caspase 3 ◽  
Intestinal Barrier ◽  
Cell Types ◽  
Innate Immune ◽  
Intestinal Epithelial ◽  
Direct Role ◽  
Immune Mediated ◽  
Significant Difference

Background and Hypothesis:   Intestinal epithelial cell (IEC) turnover occurs every four-to-five days. In inflammatory bowel disease (IBD), IECs undergo increased cell death due to inflammation of intestinal villi and colonic crypts. This cell death leads to increased permeability of the intestinal barrier. This study examined the pathogenesis of IBD, focusing on innate immunity using mice with spontaneous innate immune colitis. The objective was to observe if there is a significant difference in expression of apoptosis in colitic mice vs. control mice.  Experimental Design:  Mice expressing the NF-kB inhibitor TNFAIP3 in the villi of IECs were interbred with RAG1-/- mice. TNFAIP3 x RAG1-/- (TRAG) mice developed 100% penetrant colitis by 6 weeks of age that was not observed in TNFAIP3 or RAG1-/- littermates. The presence of activated caspase-3 in distal colons was detected using immunofluorescence and quantified using ImageJ to compare differences between 4- and 8-week-old RAG vs.TRAG mice.   Results:  Increased numbers of caspase-3+ cells were found in TRAG mice compared to RAG mice. After treatment with antibiotics, similar levels of capase-3 were detected in both groups.   Conclusion and Potential Impact:  This investigation suggests that cell death in TRAG mice were increased due to deficient innate immunity in IECs. Thus, bacteria play a direct role by killing IECs or an indirect role by causing inflammation. Understanding how innate immune activation drives cell death in IECs, may lead to a better understanding of the complex regulation of IBD, and improved therapeutic agents targeting novel cell types in the remission of chronic IBD. 

scholarly journals Apoptosis as a Mechanism for Keratinocyte Death in Canine Toxic Epidermal Necrolysis

2016 ◽  
Vol 54 (2) ◽  
pp. 249-253 ◽  
Author(s):  
F. Banovic ◽  
S. Dunston ◽  
K. E. Linder ◽  
P. Rakich ◽  
T. Olivry
Keyword(s):  
Cell Death ◽  
Toxic Epidermal Necrolysis ◽  
Caspase 3 ◽  
Skin Lesions ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Epidermal Keratinocytes ◽  
Biopsy Specimens ◽  
Significant Difference ◽  
Keratinocyte Cell ◽  
Life Threatening

In humans and dogs, toxic epidermal necrolysis (TEN) is a life-threatening dermatosis characterized by sudden epidermal death resulting in extensive skin detachment. There is little information on the pathogenesis of keratinocyte cell death in canine TEN. We studied the occurrence of apoptosis in skin lesions of dogs with TEN to determine if apoptosis contributes to the pathogenesis of this disease. Immunostaining with antibodies to activated caspase-3 and the terminal deoxynucleotidyl-transferase (TdT)–mediated deoxyuridine triphosphate (dUTP) nick-end labeling technique revealed positive apoptotic keratinocytes in basal and suprabasal epidermal compartments in 17 biopsy specimens collected from 3 dogs with TEN and 16 from 3 dogs with erythema multiforme (EM). There was no significant difference in the number of positively stained epidermal cells between TEN and EM. These results suggest that apoptosis of epidermal keratinocytes and lymphocytic satellitosis represent one of the early steps in the pathogenesis of canine TEN, as in the human disease counterpart.

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.

scholarly journals Extracellular Vesicles in Inflammatory Bowel Disease: Small Particles, Big Players

2020 ◽  
Author(s):  
M Valter ◽  
S Verstockt ◽  
J A Finalet Ferreiro ◽  
I Cleynen
Keyword(s):  
Inflammatory Bowel Disease ◽  
Extracellular Vesicles ◽  
Bowel Disease ◽  
Intestinal Barrier ◽  
Cell Types ◽  
Physiological Status ◽  
Intestinal Epithelial ◽  
Functional Roles ◽  
Physiological Processes ◽  
Inflammatory Bowel

Abstract Extracellular vesicles are nanovesicles released by many cell types into the extracellular space. They are important mediators of intercellular communication, enabling the functional transfer of molecules from one cell to another. Moreover, their molecular composition reflects the physiological status of the producing cell and tissue. Consequently, these vesicles have been involved in many [patho]physiological processes such as immunomodulation and intestinal epithelial repair, both key processes involved in inflammatory bowel disease. Given that these vesicles are present in many body fluids, they also provide opportunities for diagnostic, prognostic, and therapeutic applications. In this review, we summarise functional roles of extracellular vesicles in health and disease, with a focus on immune regulation and intestinal barrier integrity, and review recent studies on extracellular vesicles and inflammatory bowel disease. We also elaborate on their clinical potential in inflammatory bowel disease.

scholarly journals Effects of Acanthopanax senticosus supplementation on innate immunity and changes of related immune factors in healthy mice

2020 ◽  
pp. 175342592095520
Author(s):  
YunQiang Zhang ◽  
YunLu Zhang ◽  
ZiKui Liu
Keyword(s):  
Innate Immunity ◽  
Growth Performance ◽  
Innate Immune ◽  
Secretory Iga ◽  
Mouse Serum ◽  
Control Group ◽  
Dependent Manner ◽  
Acanthopanax Senticosus ◽  
Significant Difference ◽  
Immune Factors

Modern scientific research has shown that Acanthopanax senticosus (AS) can regulate the innate immunity of healthy animals, thus affecting the health of animals. However, there are few systematic reports on the changes of innate immune indices of healthy animals after consuming AS. The purpose of this project was to study the effect on healthy mice’s innate immunity and changes of related immune factors induced by feeding AS root powder supplementation. The results showed that the killing rate of natural cells increased in a dose-dependent manner in a certain time period. Compared to the control group, the treatment groups (T1, T2 and T3) improved significantly in the innate immune index (lysozyme, β-defensin-2 and duodenal secretory IgA (SIgA) to varying degrees) and induced corresponding changes of immune factors at certain time periods. The correlation between SIgA and IFN-γ in mouse serum was enhanced, and the higher the concentration of AS in the diet, the stronger the correlation was. However, there was no significant difference in growth performance among groups. It is proved that AS supplementation can enhance innate immunity and change several relevant immune factors and cells of healthy mice without affecting growth performance.

scholarly journals Brain-Derived Neurotrophic Factor Modulates Intestinal Barrier by Inhibiting Intestinal Epithelial Cells Apoptosis in Mice

2018 ◽  
pp. 475-485 ◽  
Author(s):  
D.-Y. ZHAO ◽  
W.-X. ZHANG ◽  
Q.-Q. QI ◽  
X. LONG ◽  
X. LI ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Colonic Mucosa ◽  
Caspase 3 ◽  
Intestinal Epithelial Cells ◽  
Intestinal Barrier ◽  
Intestinal Epithelial ◽  
Tight Junction Proteins ◽  
Intestinal Barrier Integrity ◽  
Junction Proteins ◽  
Active Caspase

We aimed to investigate the effects of brain-derived neurotrophic factor (BDNF) on apoptosis of intestinal epithelial cells (IECs) and alterations of intestinal barrier integrity using BDNF knock-out mice model. Colonic tissues from BDNF+/+ mice and BDNF+/- mice were prepared for this study. The integrity of colonic mucosa was evaluated by measuring trans-mucosa electrical resistance and tissue conductance in Ussing chamber. The colonic epithelial structure was analyzed by transmission electron microscopy. Apoptosis involvement was determined with TUNEL staining, active caspase-3 immunostaining and Western blotting for the protein expression of active caspase-3, Bax and Bcl-2. The expression levels and distribution of tight junction proteins were evaluated by immunohistochemistry or Western blots. Compared with BDNF+/+ mice, BDNF+/- mice displayed impaired integrity and ultrastructure alterations in their colonic mucosa, which was characterized by diminished microvilli, mitochondrial swelling and epithelial cells apoptosis. Altered intestinal barrier function was linked to excessive apoptosis of IECs demonstrated by the higher proportion of TUNEL-positive apoptotic cells and enhanced caspase activities in BDNF+/- mice. Increased expression of Bax and claudin-2 proteins and reduced Bcl-2 and tight junction proteins (occludin, ZO-1 and claudin-1) expression were also detected in the colonic mucosa of BDNF+/- mice. BDNF may play a role in the maintenance of intestinal barrier integrity via its anti-apoptotic properties.

scholarly journals The cell biology of inflammation: From common traits to remarkable immunological adaptations

2020 ◽  
Vol 219 (7) ◽  
Author(s):  
Helen Weavers ◽  
Paul Martin
Keyword(s):  
Innate Immunity ◽  
Cell Division ◽  
Membrane Trafficking ◽  
Immune Cells ◽  
Cell Biology ◽  
Foreign Bodies ◽  
Cell Types ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Starting Point

Tissue damage triggers a rapid and robust inflammatory response in order to clear and repair a wound. Remarkably, many of the cell biology features that underlie the ability of leukocytes to home in to sites of injury and to fight infection—most of which are topics of intensive current research—were originally observed in various weird and wonderful translucent organisms over a century ago by Elie Metchnikoff, the “father of innate immunity,” who is credited with discovering phagocytes in 1882. In this review, we use Metchnikoff’s seminal lectures as a starting point to discuss the tremendous variety of cell biology features that underpin the function of these multitasking immune cells. Some of these are shared by other cell types (including aspects of motility, membrane trafficking, cell division, and death), but others are more unique features of innate immune cells, enabling them to fulfill their specialized functions, such as encapsulation of invading pathogens, cell–cell fusion in response to foreign bodies, and their self-sacrifice as occurs during NETosis.

scholarly journals Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity

2015 ◽  
Vol 212 (10) ◽  
pp. 1513-1528 ◽  
Author(s):  
Paul R. Giacomin ◽  
Ryan H. Moy ◽  
Mario Noti ◽  
Lisa C. Osborne ◽  
Mark C. Siracusa ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Epithelial Cell ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Lymphoid Cells ◽  
Intestinal Damage ◽  
Intestinal Epithelial ◽  
Mucosal Surfaces ◽  
Host Mortality ◽  
Group 3

Innate lymphoid cells (ILCs) are critical for maintaining epithelial barrier integrity at mucosal surfaces; however, the tissue-specific factors that regulate ILC responses remain poorly characterized. Using mice with intestinal epithelial cell (IEC)–specific deletions in either inhibitor of κB kinase (IKK)α or IKKβ, two critical regulators of NFκB activation, we demonstrate that IEC-intrinsic IKKα expression selectively regulates group 3 ILC (ILC3)–dependent antibacterial immunity in the intestine. Although IKKβΔIEC mice efficiently controlled Citrobacter rodentium infection, IKKαΔIEC mice exhibited severe intestinal inflammation, increased bacterial dissemination to peripheral organs, and increased host mortality. Consistent with weakened innate immunity to C. rodentium, IKKαΔIEC mice displayed impaired IL-22 production by RORγt+ ILC3s, and therapeutic delivery of rIL-22 or transfer of sort-purified IL-22–competent ILCs from control mice could protect IKKαΔIEC mice from C. rodentium–induced morbidity. Defective ILC3 responses in IKKαΔIEC mice were associated with overproduction of thymic stromal lymphopoietin (TSLP) by IECs, which negatively regulated IL-22 production by ILC3s and impaired innate immunity to C. rodentium. IEC-intrinsic IKKα expression was similarly critical for regulation of intestinal inflammation after chemically induced intestinal damage and colitis. Collectively, these data identify a previously unrecognized role for epithelial cell–intrinsic IKKα expression and TSLP in regulating ILC3 responses required to maintain intestinal barrier immunity.

scholarly journals Apoptosis, Necrosis, and Necroptosis in the Gut and Intestinal Homeostasis

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Anna Negroni ◽  
Salvatore Cucchiara ◽  
Laura Stronati
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Intestinal Epithelial Cells ◽  
Inflammatory Diseases ◽  
Intestinal Barrier ◽  
Intestinal Lumen ◽  
Intestinal Epithelial ◽  
Commensal Microbiota ◽  
Adaptive Immune ◽  
Epithelial Cell Death

Intestinal epithelial cells (IECs) form a physiochemical barrier that separates the intestinal lumen from the host’s internal milieu and is critical for electrolyte passage, nutrient absorption, and interaction with commensal microbiota. Moreover, IECs are strongly involved in the intestinal mucosal inflammatory response as well as in mucosal innate and adaptive immune responses. Cell death in the intestinal barrier is finely controlled, since alterations may lead to severe disorders, including inflammatory diseases. The emerging picture indicates that intestinal epithelial cell death is strictly related to the maintenance of tissue homeostasis. This review is focused on previous reports on different forms of cell death in intestinal epithelium.

Abstract 59: Post-stroke Delivery of Microrna-363 to Middle-aged Female Rats is Internalized by Neurons and Suppresses the Cell Death Effector Pathway

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Amutha Selvamani ◽  
Farida Sohrabji
Keyword(s):  
Cell Death ◽  
Caspase 3 ◽  
Infarct Volume ◽  
Cell Types ◽  
Female Rats ◽  
Middle Aged ◽  
Stroke Outcomes ◽  
Post Stroke ◽  
Double Label ◽  
Death Effector

Background: MicroRNAs serve as translational inhibitors and offer a unique therapeutic target for acute diseases such as stroke. Profiling of circulating miRNA after stroke identified mir363, whose expression was inversely correlated with infarct volume. Middle aged female rats show worse stroke outcomes than younger females and have much lower levels of mir363. Our recent studies showed that iv injections of miR363 mimic to middle aged females, significantly improved stroke outcome. The present study is designed to determine the mechanisms by which miR-363 acts as a therapeutic miR. Methods: Middle aged (12 mo) females were subject to MCAo. At 4h post-stroke, animals received a tail-vein injection of miR-363-3p FAM or scrambled control. Animals were terminated at 48h or 5d post-MCAo and perfused transcardially or processed for protein, respectively. To determine which neural cell types localized exogenous mir363-3p, combined immunofluorescence was performed for cell specific markers (neuronal (NeuN), astrocytic (GFAP), microglial (CD11b) and endothelial (PECAM)) and mir363-3p-FAM mimic on coronal brain sections (25 mm thickness). Protein lysates from the ischemic tissue was analyzed for caspase-3 expression by Western blot analysis. Results: FAM-labeled mir363-3p was widely detected in the forebrain. The majority of NeuN+ cells in the cortex and striatum were also labeled with FAM-363-3p, indicating a robust internalization of the mimic in neurons. FAM-mir363-3p was also localized to a few microglia (CD11b +), virtually no double-label was seen in astrocytes and endothelial cells. Mir363 decreased the expression and functional activity of caspase3 in the ischemic hemisphere. Conclusion: Collectively, the data suggests that exogenous miR-363-3p is shuttled to the brain and is preferentially internalized by neurons. Together with the caspase-3 regulation, our data suggests that mir363 may improve stroke outcomes by suppressing a cell death effector.

Are caspases involved in the death of cells with a transcriptionally inactive nucleus? Sperm and chicken erythrocytes

1998 ◽  
Vol 111 (18) ◽  
pp. 2707-2715 ◽  
Author(s):  
M. Weil ◽  
M.D. Jacobson ◽  
M.C. Raff
Keyword(s):  
Cell Death ◽  
Caspase 3 ◽  
Cell Types ◽  
Cell System ◽  
Caspase Inhibitor ◽  
Mouse Sperm ◽  
Caspase Inhibitors ◽  
Protein Components ◽  
Chicken Erythrocytes ◽  
Suicide Mechanism

We show that mouse sperm die spontaneously within 1–2 days in culture and that treatment with either staurosporine (STS) and cycloheximide (CHX) or a peptide caspase inhibitor does not accelerate or delay the cell death. Chicken erythrocytes, by contrast, are induced to die by either serum deprivation or treatment with STS and CHX, and embryonic erythrocytes are more sensitive than adult erythrocytes to both treatments. Although these erythrocyte deaths display a number of features that are characteristic of apoptosis, they are not blocked, or even delayed, by peptide caspase inhibitors, and most of the cells die without apparently activating caspases. A small proportion of the dying erythrocytes do activate caspase-3, but even these cells, which seem to be the least mature erythrocytes, die just as quickly in the presence of caspase inhibitors. Our findings raise the possibility that both mouse sperm and chicken erythrocytes have a death programme that may not depend on caspases and that chicken erythrocytes lose caspases as they mature. Chicken erythrocytes may provide a useful ‘stripped down’ cell system to try to identify the protein components of such a death programme, which may serve to back-up the conventional caspase-dependent suicide mechanism in many cell types.

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