Caspase-11 attenuates gastrointestinal inflammation and experimental colitis pathogenesis

Nucleotide-binding domain and leucine-rich repeat containing protein inflammasome formation plays an essential role in modulating immune system homeostasis in the gut. Recently, a caspase-11 noncanonical inflammasome has been characterized and appears to modulate many biological functions that were previously considered to be solely dependent on caspase-1 and the canonical inflammasome. To better elucidate the function of this noncanonical inflammasome during inflammatory bowel disease, experimental colitis was induced in wild-type and Casp11 −/− mice utilizing dextran sulfate sodium (DSS). Here, we report that caspase-11 attenuates acute experimental colitis pathogenesis. Casp11 −/− mice showed significantly increased morbidity and colon inflammation following DSS exposure. Subsequent cytokine analysis revealed that IL-1β and IL-18 levels in the colon were significantly reduced in the Casp11 −/− mice compared with the wild-type animals. Additional mechanistic studies utilizing IL-1β and IL-18 reconstitution revealed that Casp11 −/− hypersensitivity was associated with the loss of both of these cytokines. Bone marrow reconstitution experiments further revealed that caspase-11 gene expression and function in both hematopoietic- and nonhematopoietic-derived cells contribute to disease attenuation. Interestingly, unlike caspase-1, caspase-11 does not appear to influence relapsing remitting disease progression or the development of colitis-associated tumorigenesis. Together, these data identify caspase-11 as a critical factor protecting the host during acute DSS-induced colonic injury and inflammation but not during chronic inflammation and tumorigenesis.

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Hyaluronan Synthase 3 Null Mice Exhibit Decreased Intestinal Inflammation and Tissue Damage in the DSS-Induced Colitis Model

International Journal of Cell Biology ◽

10.1155/2015/745237 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 23

Author(s):

Sean P. Kessler ◽

Dana R. Obery ◽

Carol de la Motte

Keyword(s):

Intestinal Inflammation ◽

Inflammatory Diseases ◽

Experimental Colitis ◽

Hyaluronan Synthase ◽

Wild Type ◽

Colon Tissue ◽

Dss Colitis ◽

Chemically Induced ◽

Inflammatory Bowel ◽

Colitis Model

Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD). Hyaluronan can act as a leukocyte recruitment molecule and in the most common mouse model of intestinal inflammation, the chemically induced dextran sodium sulfate (DSS) experimental colitis model, we previously determined that changes in colon distribution of HA occur before inflammation. Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation. In this study, we tested the progression of inflammation in mice null for the hyaluronan synthase genes (HAS1, HAS3, or both HAS1 and HAS3) in the DSS-colitis model. Our data demonstrate that both the HAS1/HAS3 double and the HAS3 null mice are protected from colitis, compared to wild-type and HAS1 null mice, as determined by measurement of weight loss, disease activity, serum IL-6 levels, histologic scoring, and immunohistochemistry. Most notable is the dramatic increase in submucosal microvasculature, hyaluronan deposition, and leukocyte infiltration in the inflamed colon tissue of wild-type and HAS1 null mice. Our data suggest, HAS3 plays a crucial role in driving gut inflammation. Developing a temporary targeted therapeutic intervention of HAS3 expression or function in the microcirculation may emerge as a desirable strategy toward tempering colitis in patients undergoing flares of IBD.

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Tissue-Resident T Cells in Chronic Relapsing–Remitting Intestinal Disorders

Cells ◽

10.3390/cells10081882 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1882

Author(s):

Juliana Barreto de Albuquerque ◽

Christoph Mueller ◽

Bilgi Gungor

Keyword(s):

Rheumatoid Arthritis ◽

Multiple Sclerosis ◽

Cell Biology ◽

Critical Factor ◽

Therapeutic Strategies ◽

Inflammatory Disorders ◽

Relapsing Remitting ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Barrier Tissues

Tissue-resident memory T (TRM) cells critically contribute to the rapid immunoprotection and efficient immunosurveillance against pathogens, particularly in barrier tissues, but also during anti-tumor responses. However, the involvement of TRM cells also in the induction and exacerbation of immunopathologies, notably in chronically relapsing auto-inflammatory disorders, is becoming increasingly recognized as a critical factor. Thus, TRM cells may also represent an attractive target in the management of chronic (auto-) inflammatory disorders, including multiple sclerosis, rheumatoid arthritis, celiac disease and inflammatory bowel diseases. In this review, we focus on current concepts of TRM cell biology, particularly in the intestine, and discuss recent findings on their involvement in chronic relapsing–remitting inflammatory disorders. Potential therapeutic strategies to interfere with these TRM cell-mediated immunopathologies are discussed.

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Effects of N-acetylcysteine Treatment on Oxidative Stress in Acetic Acid-induced Experimental Colitis in Rats

Journal of International Medical Research ◽

10.1177/147323000503300207 ◽

2005 ◽

Vol 33 (2) ◽

pp. 196-206 ◽

Cited By ~ 35

Author(s):

E Akgun ◽

C Çaliskan ◽

HA Celik ◽

AO Ozutemiz ◽

M Tuncyurek ◽

...

Keyword(s):

Nitric Oxide ◽

Acetic Acid ◽

Experimental Colitis ◽

Rat Colon ◽

Protective Effects ◽

Colonic Injury ◽

Toxic Damage ◽

Standard Assay ◽

Inflammatory Bowel ◽

Acid Administration

We assessed the possible protective effects of N-acetylcysteine (NAC) against toxic damage in the rat colon. Two doses of NAC (20 mg/kg and 100 mg/kg) given for 2 days and 7 days after acetic acid administration (to induce colitis) were tested. NAC was dissolved in saline and administered locally (intracolonic), systemically (intraperitoneal) or in a combination (intracolonic and intraperitoneal). Several parameters, including macroscopic and histopathological scores and myeloperoxidase, glutathione and nitric oxide concentrations were measured using standard assay procedures. Treatment with 100 mg/kg NAC for 7 days significantly decreased tissue myeloperoxidase, glutathione and nitric oxide concentrations. The 20 mg/kg dose had no protective effects. The data indicate that NAC substantially reduced the degree of colonic injury, probably by regulating free radical production and inhibiting inflammation. It may, therefore, have a role in the treatment of inflammatory bowel disease.

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The NALCN Channel Regulator UNC-80 Functions in a Subset of Interneurons To Regulate Caenorhabditis elegans Reversal Behavior

G3 Genes|Genome|Genetics ◽

10.1534/g3.119.400692 ◽

2019 ◽

Vol 10 (1) ◽

pp. 199-210 ◽

Cited By ~ 1

Author(s):

Chuanman Zhou ◽

Jintao Luo ◽

Xiaohui He ◽

Qian Zhou ◽

Yunxia He ◽

...

Keyword(s):

Plant Hormone ◽

Neuronal Excitability ◽

Resting Membrane Potential ◽

Loss Of Function ◽

Wild Type ◽

C Elegans ◽

Link Type ◽

Complex Functions ◽

And Function ◽

Multiple Loss

NALCN (Na+leak channel, non-selective) is a conserved, voltage-insensitive cation channel that regulates resting membrane potential and neuronal excitability. UNC79 and UNC80 are key regulators of the channel function. However, the behavioral effects of the channel complex are not entirely clear and the neurons in which the channel functions remain to be identified. In a forward genetic screen for C. elegans mutants with defective avoidance response to the plant hormone methyl salicylate (MeSa), we isolated multiple loss-of-function mutations in unc-80 and unc-79. C. elegans NALCN mutants exhibited similarly defective MeSa avoidance. Interestingly, NALCN, unc-80 and unc-79 mutants all showed wild type-like responses to other attractive or repelling odorants, suggesting that NALCN does not broadly affect odor detection or related forward and reversal behaviors. To understand in which neurons the channel functions, we determined the identities of a subset of unc-80-expressing neurons. We found that unc-79 and unc-80 are expressed and function in overlapping neurons, which verified previous assumptions. Neuron-specific transgene rescue and knockdown experiments suggest that the command interneurons AVA and AVE and the anterior guidepost neuron AVG can play a sufficient role in mediating unc-80 regulation of the MeSa avoidance. Though primarily based on genetic analyses, our results further imply that MeSa might activate NALCN by direct or indirect actions. Altogether, we provide an initial look into the key neurons in which the NALCN channel complex functions and identify a novel function of the channel in regulating C. elegans reversal behavior through command interneurons.

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The Drosophila engrailed and invected Genes: Partners in Regulation, Expression and Function

Genetics ◽

10.1093/genetics/142.3.893 ◽

1996 ◽

Vol 142 (3) ◽

pp. 893-906 ◽

Cited By ~ 3

Author(s):

Elizabeth Gustavson ◽

Andrew S Goldsborough ◽

Zehra Ali ◽

Thomas B Kornberg

Keyword(s):

Expression Pattern ◽

Cultured Cells ◽

Regulatory Region ◽

Embryonic Lethality ◽

Wild Type ◽

Terminal Portion ◽

Coding Sequence ◽

Differential Effects ◽

And Function ◽

Redundant Functions

Abstract We isolated and characterized numerous engrailed and invected alleles. Among the deficiencies we isolated, a mutant lacking invected sequences was viable and phenotypically normal, a mutant lacking engrailed was an embryo lethal and had slight segmentation defects, and a mutant lacking both engrailed and invected was most severely affected. In seven engrailed alleles, mutations caused translation to terminate prematurely in the central or C-terminal portion of the coding sequence, resulting in embryonic lethality and segmentation defects. Both engrailed and invected expression declined prematurely in these mutant embryos. In wild-type embryos, engrailed and invected are juxtaposed and are expressed in essentially identical patterns. A breakpoint mutant that separates the mgrailed and invected transcription units parceled different aspects of the expression pattern to engrailed or invected. We also found that both genes cause similar defects when expressed ectopically and that the protein products of both genes act to repress transcription in cultured cells. We propose that the varied phenotypes of the engrailed alleles can be explained by the differential effects these mutants have on the combination of engrailed and invected activities, that engrailed and invected share a regulatory region, and that they encode redundant functions.

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Rootstocks Overexpressing StNPR1 and StDREB1 Improve Osmotic Stress Tolerance of Wild-Type Scion in Transgrafted Tobacco Plants

International Journal of Molecular Sciences ◽

10.3390/ijms22168398 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8398

Author(s):

Yasmine S. Hezema ◽

Mukund R. Shukla ◽

Alok Goel ◽

Murali M. Ayyanath ◽

Sherif M. Sherif ◽

...

Keyword(s):

Osmotic Stress ◽

Transgenic Tobacco ◽

Physiological Status ◽

Wild Type ◽

Long Distance ◽

Graft Union ◽

Tobacco Plants ◽

Osmotic Stress Tolerance ◽

And Function ◽

Gene Expression Levels

In grafted plants, the movement of long-distance signals from rootstocks can modulate the development and function of the scion. To understand the mechanisms by which tolerant rootstocks improve scion responses to osmotic stress (OS) conditions, mRNA transport of osmotic responsive genes (ORGs) was evaluated in a tomato/potato heterograft system. In this system, Solanum tuberosum was used as a rootstock and Solanum lycopersicum as a scion. We detected changes in the gene expression levels of 13 out of the 21 ORGs tested in the osmotically stressed plants; of these, only NPR1 transcripts were transported across the graft union under both normal and OS conditions. Importantly, OS increased the abundance of StNPR1 transcripts in the tomato scion. To examine mRNA mobility in transgrafted plants, StNPR1 and StDREB1 genes representing the mobile and non-mobile transcripts, respectively, were overexpressed in tobacco (Nicotiana tabacum). The evaluation of transgenic tobacco plants indicated that overexpression of these genes enhanced the growth and improved the physiological status of transgenic plants growing under OS conditions induced by NaCl, mannitol and polyethylene glycol (PEG). We also found that transgenic tobacco rootstocks increased the OS tolerance of the WT-scion. Indeed, WT scions on transgenic rootstocks had higher ORGs transcript levels than their counterparts on non-transgenic rootstocks. However, neither StNPR1 nor StDREB1 transcripts were transported from the transgenic rootstock to the wild-type (WT) tobacco scion, suggesting that other long-distance signals downstream these transgenes could have moved across the graft union leading to OS tolerance. Overall, our results signify the importance of StNPR1 and StDREB1 as two anticipated candidates for the development of stress-resilient crops through transgrafting technology.

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Breeder Diet Strategies for Generating Ttpa-Null and Wild-Type Mice with Low Vitamin E Status to Assess Neurological Outcomes

Current Developments in Nutrition ◽

10.1093/cdn/nzaa155 ◽

2020 ◽

Vol 4 (11) ◽

Author(s):

Katherine M Ranard ◽

Matthew J Kuchan ◽

John W Erdman

Keyword(s):

Animal Model ◽

Vitamin E ◽

Mouse Model ◽

Wild Type ◽

Future Studies ◽

Neurological Outcomes ◽

Transfer Protein ◽

And Function ◽

The Brain ◽

Vitamin E Status

ABSTRACT Studying vitamin E [α-tocopherol (α-T)] metabolism and function in the brain and other tissues requires an animal model with low α-T status, such as the transgenic α-T transfer protein (Ttpa)–null (Ttpa−/−) mouse model. Ttpa+/− dams can be used to produce Ttpa−/− and Ttpa+/+mice for these studies. However, the α-T content in Ttpa+/− dams’ diet requires optimization; diets must provide sufficient α-T for reproduction, while minimizing the transfer of α-T to the offspring destined for future studies that require low baseline α-T status. The goal of this work was to assess the effectiveness and feasibility of 2 breeding diet strategies on reproduction outcomes and offspring brain α-T concentrations. These findings will help standardize the breeding methodology used to generate the Ttpa−/− mice for neurological studies.

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Overview of Inositol and Inositol Phosphates on Chemoprevention of Colitis-Induced Carcinogenesis

Molecules ◽

10.3390/molecules26010031 ◽

2020 ◽

Vol 26 (1) ◽

pp. 31

Author(s):

Samuel E. Weinberg ◽

Le Yu Sun ◽

Allison L. Yang ◽

Jie Liao ◽

Guang Yu Yang

Keyword(s):

Inositol Phosphates ◽

Human Cancer ◽

Energy Transduction ◽

Nutritional Deficiencies ◽

Increased Risk ◽

Rna Export ◽

Inflammatory Bowel ◽

And Function ◽

Biologic Function ◽

Atp Regeneration

Chronic inflammation is one of the most common and well-recognized risk factors for human cancer, including colon cancer. Inflammatory bowel disease (IBD) is defined as a longstanding idiopathic chronic active inflammatory process in the colon, including ulcerative colitis and Crohn’s disease. Importantly, patients with IBD have a significantly increased risk for the development of colorectal carcinoma. Dietary inositol and its phosphates, as well as phospholipid derivatives, are well known to benefit human health in diverse pathologies including cancer prevention. Inositol phosphates including InsP3, InsP6, and other pyrophosphates, play important roles in cellular metabolic and signal transduction pathways involved in the control of cell proliferation, differentiation, RNA export, DNA repair, energy transduction, ATP regeneration, and numerous others. In the review, we highlight the biologic function and health effects of inositol and its phosphates including the nature and sources of these molecules, potential nutritional deficiencies, their biologic metabolism and function, and finally, their role in the prevention of colitis-induced carcinogenesis.

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A Rubisco-binding protein is required for normal pyrenoid number and starch sheath morphology inChlamydomonas reinhardtii

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1904587116 ◽

2019 ◽

Vol 116 (37) ◽

pp. 18445-18454 ◽

Cited By ~ 14

Author(s):

Alan K. Itakura ◽

Kher Xing Chan ◽

Nicky Atkinson ◽

Leif Pallesen ◽

Lianyong Wang ◽

...

Keyword(s):

Surface Area ◽

Structure And Function ◽

Binding Motif ◽

Starch Granules ◽

Wild Type ◽

Bisphosphate Carboxylase ◽

Biophysical Mechanism ◽

Mechanism Function ◽

And Function

A phase-separated, liquid-like organelle called the pyrenoid mediates CO2fixation in the chloroplasts of nearly all eukaryotic algae. While most algae have 1 pyrenoid per chloroplast, here we describe a mutant in the model algaChlamydomonasthat has on average 10 pyrenoids per chloroplast. Characterization of the mutant leads us to propose a model where multiple pyrenoids are favored by an increase in the surface area of the starch sheath that surrounds and binds to the liquid-like pyrenoid matrix. We find that the mutant’s phenotypes are due to disruption of a gene, which we call StArch Granules Abnormal 1 (SAGA1) because starch sheath granules, or plates, in mutants lacking SAGA1 are more elongated and thinner than those of wild type. SAGA1 contains a starch binding motif, suggesting that it may directly regulate starch sheath morphology. SAGA1 localizes to multiple puncta and streaks in the pyrenoid and physically interacts with the small and large subunits of the carbon-fixing enzyme Rubisco (ribulose-1,5-bisphosphate carboxylase/oxygenase), a major component of the liquid-like pyrenoid matrix. Our findings suggest a biophysical mechanism by which starch sheath morphology affects pyrenoid number and CO2-concentrating mechanism function, advancing our understanding of the structure and function of this biogeochemically important organelle. More broadly, we propose that the number of phase-separated organelles can be regulated by imposing constraints on their surface area.

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DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1906565116 ◽

2019 ◽

Vol 116 (50) ◽

pp. 25322-25328 ◽

Cited By ~ 20

Author(s):

Yi Liu ◽

Xiaopin Ma ◽

Hisashi Fujioka ◽

Jun Liu ◽

Shengdi Chen ◽

...

Keyword(s):

Autosomal Recessive ◽

Cellular Mechanism ◽

Loss Of Function ◽

Wild Type ◽

Calcium Efflux ◽

And Function ◽

The Brain ◽

Early Onset Parkinson’S Disease

Loss-of-function mutations in DJ-1 are associated with autosomal recessive early onset Parkinson’s disease (PD), yet the underlying pathogenic mechanism remains elusive. Here we demonstrate that DJ-1 localized to the mitochondria-associated membrane (MAM) both in vitro and in vivo. In fact, DJ-1 physically interacts with and is an essential component of the IP3R3-Grp75-VDAC1 complexes at MAM. Loss of DJ-1 disrupted the IP3R3-Grp75-VDAC1 complex and led to reduced endoplasmic reticulum (ER)-mitochondria association and disturbed function of MAM and mitochondria in vitro. These deficits could be rescued by wild-type DJ-1 but not by the familial PD-associated L166P mutant which had demonstrated reduced interaction with IP3R3-Grp75. Furthermore, DJ-1 ablation disturbed calcium efflux-induced IP3R3 degradation after carbachol treatment and caused IP3R3 accumulation at the MAM in vitro. Importantly, similar deficits in IP3R3-Grp75-VDAC1 complexes and MAM were found in the brain of DJ-1 knockout mice in vivo. The DJ-1 level was reduced in the substantia nigra of sporadic PD patients, which was associated with reduced IP3R3-DJ-1 interaction and ER-mitochondria association. Together, these findings offer insights into the cellular mechanism in the involvement of DJ-1 in the regulation of the integrity and calcium cross-talk between ER and mitochondria and suggests that impaired ER-mitochondria association could contribute to the pathogenesis of PD.

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