scholarly journals Toll-Like Receptor-4 Is Involved in Mediating Intestinal and Extra-Intestinal Inflammation in Campylobacter coli-Infected Secondary Abiotic IL-10−/− Mice

2020 ◽  
Vol 8 (12) ◽  
pp. 1882
Author(s):  
Sigri Kløve ◽  
Claudia Genger ◽  
Dennis Weschka ◽  
Soraya Mousavi ◽  
Stefan Bereswill ◽  
...  
Keyword(s):  
Immune Responses ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Clinical Signs ◽  
Campylobacter Coli ◽  
Toll Like Receptor ◽  
Host Interactions ◽  
Non Invasive ◽  
Health Burdens

Human Campylobacter infections are emerging worldwide and constitute significant health burdens. We recently showed that the immunopathological sequelae in Campylobacter jejuni-infected mice were due to Toll-like receptor (TLR)-4 dependent immune responses induced by bacterial lipooligosaccharide (LOS). Information regarding the molecular mechanisms underlying Campylobacter coli-host interactions are scarce, however. Therefore, we analyzed C. coli-induced campylobacteriosis in secondary abiotic IL-10−/− mice with and without TLR4. Mice were infected perorally with a human C. coli isolate or with a murine commensal Escherichia coli as apathogenic, non-invasive control. Independent from TLR4, C. coli and E. coli stably colonized the gastrointestinal tract, but only C. coli induced clinical signs of campylobacteriosis. TLR4−/− IL-10−/− mice, however, displayed less frequently fecal blood and less distinct histopathological and apoptotic sequelae in the colon versus IL-10−/− counterparts on day 28 following C. coli infection. Furthermore, C. coli-induced colonic immune cell responses were less pronounced in TLR4−/− IL-10−/− as compared to IL-10−/− mice and accompanied by lower pro-inflammatory mediator concentrations in the intestines and the liver of the former versus the latter. In conclusion, our study provides evidence that TLR4 is involved in mediating C. coli-LOS-induced immune responses in intestinal and extra-intestinal compartments during murine campylobacteriosis.

scholarly journals Inflammatory Immune Responses and Gut Microbiota Changes Following Campylobacter coli Infection of IL-10-/- Mice with Chronic Colitis

Pathogens ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 560
Author(s):  
Markus M. Heimesaat ◽  
Claudia Genger ◽  
Nina Biesemeier ◽  
Sigri Klove ◽  
Dennis Weschka ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Immune Responses ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Underlying Disease ◽  
Campylobacter Coli ◽  
Chronic Colitis ◽  
Host Interactions ◽  
Human Infections ◽  
Gastrointestinal Colonization

Human infections with the food-borne enteropathogens Campylobacter are progressively rising. Recent evidence revealed that pre-existing intestinal inflammation facilitates enteropathogenic infection subsequently exacerbating the underlying disease. Given that only little is known about C. coli–host interactions and particularly during intestinal inflammation, the aim of the present study was to survey gastrointestinal colonization properties, gut microbiota changes and pro-inflammatory sequelae upon peroral C. coli-infection of IL-10-/- mice with chronic colitis. C. coli colonized the gastrointestinal tract of mice with varying efficiencies until day 28 post-infection and induced macroscopic and microscopic inflammatory changes as indicated by shorter colonic lengths, more distinct histopathological changes in the colonic mucosa and higher numbers of apoptotic colonic epithelial cells when compared to mock-infected controls. Furthermore, not only colonic innate and adaptive immune cell responses, but also enhanced systemic TNF-α secretion could be observed following C. coli as opposed to mock challenge. Notably, C. coli induced intestinal inflammatory sequelae were accompanied with gut microbiota shifts towards higher commensal enterobacterial loads in the infected gut lumen. Moreover, the pathogen translocated from the intestinal tract to extra-intestinal tissue sites in some cases, but never to systemic compartments. Hence, C. coli accelerates inflammatory immune responses in IL-10-/- mice with chronic colitis.

scholarly journals Toll-Like Receptor-4 Dependent Intestinal and Systemic Sequelae Following Peroral Campylobacter coli Infection of IL10 Deficient Mice Harboring a Human Gut Microbiota

Pathogens ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 386 ◽  
Author(s):  
Sigri Kløve ◽  
Claudia Genger ◽  
Soraya Mousavi ◽  
Dennis Weschka ◽  
Stefan Bereswill ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Immune Responses ◽  
Immune Cell ◽  
Fecal Microbiota Transplantation ◽  
Clinical Signs ◽  
Toll Like Receptor ◽  
Human Gut ◽  
Toll Like Receptor 4 ◽  
Host Immune Responses ◽  
Human Gut Microbiota

Zoonotic Campylobacter, including C. jejuni and C. coli, are among the most prevalent agents of food-borne enteritis worldwide. The immunopathological sequelae of campylobacteriosis are caused by Toll-like Receptor-4 (TLR4)-dependent host immune responses, induced by bacterial lipooligosaccharide (LOS). In order to investigate C. coli-host interactions, including the roles of the human gut microbiota and TLR4, upon infection, we applied a clinical acute campylobacteriosis model, and subjected secondary abiotic, TLR4-deficient IL10-/- mice and IL10-/- controls to fecal microbiota transplantation derived from human donors by gavage, before peroral C. coli challenge. Until day 21 post-infection, C. coli could stably colonize the gastrointestinal tract of human microbiota-associated (hma) mice of either genotype. TLR4-deficient IL10-/- mice, however, displayed less severe clinical signs of infection, that were accompanied by less distinct apoptotic epithelial cell and innate as well as adaptive immune cell responses in the colon, as compared to IL10-/- counterparts. Furthermore, C. coli infected IL10-/-, as opposed to TLR4-deficient IL10-/-, mice displayed increased pro-inflammatory cytokine concentrations in intestinal and, strikingly, systemic compartments. We conclude that pathogenic LOS might play an important role in inducing TLR4-dependent host immune responses upon C. coli infection, which needs to be further addressed in more detail.

scholarly journals Circulating miRNAs Related to Epithelial–Mesenchymal Transitions (EMT) as the New Molecular Markers in Endometriosis

2021 ◽  
Vol 43 (2) ◽  
pp. 900-916
Author(s):  
Anna Zubrzycka ◽  
Monika Migdalska-Sęk ◽  
Sławomir Jędrzejczyk ◽  
Ewa Brzeziańska-Lasota
Keyword(s):  
Molecular Mechanisms ◽  
Immune Cell ◽  
Epithelial Mesenchymal Transition ◽  
Clinical Symptoms ◽  
Diagnostic Tools ◽  
Endometrial Stromal Cells ◽  
Disease Etiology ◽  
Diagnostic Biomarkers ◽  
Mesenchymal Transition ◽  
Non Invasive

Endometriosis is a chronic gynecological disease defined by the presence of endometrial-like tissue found outside the uterus, most commonly in the peritoneal cavity. Endometriosis lesions are heterogenous but usually contain endometrial stromal cells and epithelial glands, immune cell infiltrates and are vascularized and innervated by nerves. The complex etiopathogenesis and heterogenity of the clinical symptoms, as well as the lack of a specific non-invasive diagnostic biomarkers, underline the need for more advanced diagnostic tools. Unfortunately, the contribution of environmental, hormonal and immunological factors in the disease etiology is insufficient, and the contribution of genetic/epigenetic factors is still fragmentary. Therefore, there is a need for more focused study on the molecular mechanisms of endometriosis and non-invasive diagnostic monitoring systems. MicroRNAs (miRNAs) demonstrate high stability and tissue specificity and play a significant role in modulating a range of molecular pathways, and hence may be suitable diagnostic biomarkers for the origin and development of endometriosis. Of these, the most frequently studied are those related to endometriosis, including those involved in epithelial–mesenchymal transition (EMT), whose expression is altered in plasma or endometriotic lesion biopsies; however, the results are ambiguous. Specific miRNAs expressed in endometriosis may serve as diagnostics markers with prognostic value, and they have been proposed as molecular targets for treatment. The aim of this review is to present selected miRNAs associated with EMT known to have experimentally confirmed significance, and discuss their utility as biomarkers in endometriosis.

scholarly journals 641 Spatially organized multicellular immune hubs in MMRd and MMRp colorectal cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A670-A670
Author(s):  
Jonathan Chen ◽  
Karin Pelka ◽  
Matan Hofree ◽  
Marios Giannakis ◽  
Genevieve Boland ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Mismatch Repair ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Single Cells ◽  
Large Set ◽  
Colon Tissue

BackgroundImmune responses to cancer are highly variable, with DNA mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. Almost all tumors are infiltrated with immune cells, but the types of immune responses and their effects on tumor growth, metastasis and death, vary greatly between different cancers and individual tumors. Which of the numerous cell subsets in a tumor contribute to the response, how their interactions are regulated, and how they are spatially organized within tumors remains poorly understood.MethodsTo understand the rules governing these varied responses, we transcriptionally profiled 371,223 single cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd treatment-naive patients. We developed a systematic approach to discover cell types, their underlying gene programs, and cellular communities based on single cell RNA-seq (scRNAseq) profiles and applied it to study the distinguishing features of human MMRd and MMRp colorectal cancer. Cellular communities discovered from this analysis were spatially mapped in tissue sections using multiplex RNA in situ hybridization microscopy.ResultsTo understand the basis for differential immune responses in CRC, we first determined and compared the immune cell composition of MMRd and MMRp CRC and normal colon tissue, finding dramatic remodeling between tumor and normal tissue and between MMRd and MMRp tumors, particularly within the myeloid, T cell, and stromal compartments. Among the clusters enriched in MMRd tumors were activated CXCL13+ CD8 T cells. Importantly, gene program co-variation analysis revealed multicellular networks. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage, and an MMRd-enriched immune hub within the tumor, with activated IFNG+ and CXCL13+ T cells together with malignant and myeloid cells expressing T-cell-attracting chemokines (figure 1).ConclusionsOur study provides a rich dataset of cellular states, gene programs and their transformations in tumors across a relatively large cohort of patients with colorectal cancer. Our predictions of several multicellular hubs based on co-variation of gene expression programs, and subsequent spatial localization of two major immune-malignant hubs, organizes a large set of cell states and programs into a smaller number of coordinated networks of cells and processes. Understanding the molecular mechanisms underlying these hubs, and studying their temporal and spatial regulation upon treatment will be critical for advancing cancer therapy.Ethics ApprovalThis study was approved by the DF-HCC institutional review board (protocols 03-189 and 02-240).Abstract 641 Figure 1A coordinated network of CXCL13+ T cells with myeloid and malignant cells expressing ISGs. Image shows a portion of formalin-fixed paraffin-embedded tissue from an MMRd CRC specimen stained with multiplex RNA ISH / IF for PanCK-IF, CD3E-ISH, CXCL10/CXCL11-ISH, CXCL13-ISH, and IFNG-ISH. Note IFNG+ and CXCL13+ cells in proximity to cells expressing the chemokines CXCL10/CXCL11

scholarly journals Key Player in Cardiac Hypertrophy, Emphasizing the Role of Toll-Like Receptor 4

2020 ◽  
Vol 7 ◽  
Author(s):  
Zheng Xiao ◽  
Bin Kong ◽  
Hongjie Yang ◽  
Chang Dai ◽  
Jin Fang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cardiac Hypertrophy ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
New Technologies ◽  
Immune Cell ◽  
Current Knowledge ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling

Toll-like receptor 4 (TLR4), a key pattern recognition receptor, initiates the innate immune response and leads to chronic and acute inflammation. In the past decades, accumulating evidence has implicated TLR4-mediated inflammatory response in regulation of myocardium hypertrophic remodeling, indicating that regulation of the TLR4 signaling pathway may be an effective strategy for managing cardiac hypertrophy's pathophysiology. Given TLR4's significance, it is imperative to review the molecular mechanisms and roles underlying TLR4 signaling in cardiac hypertrophy. Here, we comprehensively review the current knowledge of TLR4-mediated inflammatory response and its interaction ligands and co-receptors, as well as activation of various intracellular signaling. We also describe the associated roles in promoting immune cell infiltration and inflammatory mediator secretion, that ultimately cause cardiac hypertrophy. Finally, we provide examples of some of the most promising drugs and new technologies that have the potential to attenuate TLR4-mediated inflammatory response and prevent or reverse the ominous cardiac hypertrophy outcomes.

MicroRNAs in the regulation of immune cell functions – implications for atherosclerotic vascular disease

2012 ◽  
Vol 107 (04) ◽  
pp. 626-633 ◽  
Author(s):  
Alma Zernecke
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Chronic Inflammatory Disease ◽  
Vascular Pathology ◽  
Lipid Uptake ◽  
T Helper ◽  
Atherosclerotic Vascular Disease ◽  
Cell Functions

SummaryRegarded as a chronic inflammatory disease of the vessel wall, the development of atherosclerotic lesions is shaped by immune responses and their regulation. Macrophages and dendritic cells are positioned at the crossroad of innate and adaptive immune responses by sensing atherogenic danger signals and by taking up and presenting antigens. T helper cells and auto-antibodies produced by B cells, together with their cytokine responses in turn modulate atheroprogression. In addition, platelets contribute to atherosclerosis by multiple pathways. microRNAs (miRNAs) that post-transcriptionally regulate gene expression may thus critically control immune cell differentiation and functions during plaque evolution. This review summarises the role of miRNAs in regulating lipid uptake and expression of inflammatory mediators in monocytes/macrophages and dendritic cells, in lymphocyte functions with a focus on T helper cell responses, as well as in platelet biology, and the implications of altering these functions in vascular pathology and atherosclerosis. T systematically survey miRNA functions in controlling molecular mechanisms and immune responses in atherosclerosis holds potential for the development of novel miRNA-based strategies for therapies targeting inflammation and immunity in atherosclerosis.

scholarly journals mTOR-Dependent Stimulation of IL20RA Orchestrates Immune Cell Trafficking through Lymphatic Endothelium in Patients with Crohn’s Disease

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 924
Author(s):  
Federica Ungaro ◽  
Valentina Garlatti ◽  
Luca Massimino ◽  
Antonino Spinelli ◽  
Michele Carvello ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Leukocyte Trafficking ◽  
Lymphatic Endothelium ◽  
Chronic Inflammatory Condition

Crohn’s disease (CD) is a chronic inflammatory condition that can affect different portions of the gastrointestinal tract. Lymphatic drainage was demonstrated to be dysfunctional in CD pathogenesis, ultimately causing the failure of the resolution of intestinal inflammation. To investigate the molecular mechanisms underlying these dysfunctions, we isolated human intestinal lymphatic endothelial cells (HILECs) from surgical specimens of patients undergoing resection for complicated CD (CD HILEC) and from a disease-free margin of surgical specimens of patients undergoing resection for cancer (healthy HILEC). Both cell types underwent transcriptomic profiling, and their barrier functionality was tested using a transwell-based co-culture system between HILEC and lamina propria mononuclear cells (LPMCs). Results showed CD HILEC displayed a peculiar transcriptomic signature that highlighted mTOR signaling as an orchestrator of leukocyte trafficking through the lymphatic barrier of CD patients. Moreover, we demonstrated that LPMC transmigration through the lymphatic endothelium of patients with CD depends on the capability of mTOR to trigger interleukin 20 receptor subunit α (IL20RA)-mediated intracellular signaling. Conclusively, our study suggests that leukocyte trafficking through the intestinal lymphatic microvasculature can be controlled by modulating IL20RA, thus leading to the resolution of chronic inflammation in patients with CD.

scholarly journals The transcriptional repressor HIC1 regulates intestinal immune homeostasis

2016 ◽  
Author(s):  
Kyle Burrows ◽  
Frann Antignano ◽  
Michael Bramhall ◽  
Alistair Chenery ◽  
Sebastian Scheer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vitamin A ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Central Component ◽  
Food Antigens

ABSTRACTThe intestine is a unique immune environment that must respond to infectious organisms but remain tolerant to commensal microbes and food antigens. However, the molecular mechanisms that regulate immune cell function in the intestine remain unclear. Here we identify the POK/ZBTB family transcription factor Hypermethylated in cancer 1 (HIC1, ZBTB29) as a central component of immunity and inflammation in the intestine. HIC1 is specifically expressed in immune cells in the intestinal lamina propria (LP) in the steady state and mice with a T cell-specific deletion of HIC1 have reduced numbers of T cells in the LP. HIC1 expression is regulated by the Vitamin A metabolite retinoic acid, as mice raised on a Vitamin A-deficient diet lack HIC1-positive cells in the intestine. HIC1-deficient T cells overproduce IL-17A in vitro and in vivo, and fail to induce intestinal inflammation, identifying a critical role for HIC1 in the regulation of T cell function in the intestinal microenvironment under both homeostatic and inflammatory conditions.

scholarly journals The Crossroads of Glycoscience, Infection, and Immunology

2021 ◽  
Vol 12 ◽  
Author(s):  
Tanya R. McKitrick ◽  
Margaret E. Ackerman ◽  
Robert M. Anthony ◽  
Clay S. Bennett ◽  
Michael Demetriou ◽  
...  
Keyword(s):  
Immune Responses ◽  
Host Response ◽  
Immune Cell ◽  
Microbial Infection ◽  
Surface Receptors ◽  
Host Interactions ◽  
Host Immune Responses ◽  
Immune Mediators ◽  
Immune Mediated ◽  
And Function

Advances in experimental capabilities in the glycosciences offer expanding opportunities for discovery in the broad areas of immunology and microbiology. These two disciplines overlap when microbial infection stimulates host immune responses and glycan structures are central in the processes that occur during all such encounters. Microbial glycans mediate host-pathogen interactions by acting as surface receptors or ligands, functioning as virulence factors, impeding host immune responses, or playing other roles in the struggle between host and microbe. In the context of the host, glycosylation drives cell–cell interactions that initiate and regulate the host response and modulates the effects of antibodies and soluble immune mediators. This perspective reports on a workshop organized jointly by the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research in May 2020. The conference addressed the use of emerging glycoscience tools and resources to advance investigation of glycans and their roles in microbe-host interactions, immune-mediated diseases, and immune cell recognition and function. Future discoveries in these areas will increase fundamental scientific understanding and have the potential to improve diagnosis and treatment of infections and immune dysregulation.

scholarly journals Exposure of Microglia to Interleukin-4 Represses NF-κB-Dependent Transcription of Toll-Like Receptor-Induced Cytokines

2021 ◽  
Vol 12 ◽  
Author(s):  
Ella A. Zuiderwijk-Sick ◽  
Céline van der Putten ◽  
Raissa Timmerman ◽  
Jennifer Veth ◽  
Erica M. Pasini ◽  
...  
Keyword(s):  
Immune Responses ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Surface Protein ◽  
Innate Immune ◽  
Interleukin 4 ◽  
Transcriptional Level ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Nuclear Extracts

Interleukin (IL)-4 is a cytokine that affects both adaptive and innate immune responses. In the central nervous system, microglia express IL-4 receptors and it has been described that IL-4-exposed microglia acquire anti-inflammatory properties. We here demonstrate that IL-4 exposure induces changes in the cell surface protein expression profile of primary rhesus macaque microglia and enhances their potential to induce proliferation of T cells with a regulatory signature. Moreover, we show that Toll like receptor (TLR)-induced cytokine production is broadly impaired in IL-4-exposed microglia at the transcriptional level. IL-4 type 2 receptor-mediated signaling is shown to be crucial for the inhibition of microglial innate immune responses. TLR-induced nuclear translocalization of NF-κB appeared intact, and we found no evidence for epigenetic modulation of target genes. By contrast, nuclear extracts from IL-4-exposed microglia contained significantly less NF-κB capable of binding to its DNA consensus site. Further identification of the molecular mechanisms that underlie the inhibition of TLR-induced responses in IL-4-exposed microglia may aid the design of strategies that aim to modulate innate immune responses in the brain, for example in gliomas.

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