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New Insights into Molecular Innate Immunity

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (15 April 2023) | Viewed by 19272

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Special Issue Editors

Dr. Silvia Fischer

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Guest Editor

Department of Biochemistry, Medical School, Justus-Liebig-University, 35392 Giessen, Germany
Interests: extracellular RNA; DAMPs; Toll-like receptors; innate immunity
Special Issues, Collections and Topics in MDPI journals

Dr. Ran Xu

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Guest Editor

Department of Neurosurgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, and Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany
Interests: extracellular RNA; DAMPs; innate immunity; subarachnoid hemorrhage; heart–brain axis

Special Issue Information

Dear Colleagues,

As the first line of defense, the innate immune system recognizes microbial or viral pathogens by pathogen recognition receptors (PRRs) that bind pathogen-associated molecular pattern (PAMPs). Most PRRs also recognize danger-associated molecular patterns (DAMPs), which are released by passive or active processes under sterile conditions such as ischemic injuries. Activated PRRs trigger several intracellular signaling cascades, leading to the expression of proinflammatory cytokines, type I interferons, chemokines, and the activation of immune cells such as neutrophils to resolve infection and injury. Other mechanisms involved in innate host defense are the formation of neutrophil extracellular traps (NETs) and large chromatin structures decorated with various proteolytic enzymes, which have the ability to trap and digest pathogens and to trigger inflammation.

This Special Issue aims to demonstrate new advances in mechanisms of innate immunity and their regulation. Furthermore, biological functions, mechanisms of actions of defensins, a family of antimicrobial peptides expressed predominantly in neutrophils and epithelial cells, and the role of other cells such as platelets, endothelial cells, and mast cells in innate immune responses will be covered.

Dr. Silvia Fischer
Dr. Ran Xu
Guest Editors

Manuscript Submission Information

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Keywords

innate immunity
pathogen recognition receptors
pathogen-associated molecular patterns
danger-associated molecular patterns
neutrophil extracellular traps

Published Papers (7 papers)

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Research

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19 pages, 5650 KiB

Open AccessArticle

A Mannose Receptor from Litopenaeus vannamei Involved in Innate Immunity by Pathogen Recognition and Inflammation Regulation

by Na Guo, Yuan Liu, Qiang Hao, Mingzhe Sun and Fuhua Li

Int. J. Mol. Sci. 2023, 24(13), 10665; https://doi.org/10.3390/ijms241310665 - 26 Jun 2023

Cited by 1 | Viewed by 1068

Abstract

Mannose receptor, as a member of the C-type lectin superfamily, is a non-canonical pattern recognition receptor that can internalize pathogen-associated ligands and activate intracellular signaling. Here, a mannose receptor gene, LvMR, was identified from the Pacific white shrimp Litopenaeus vannamei. LvMR encoded a signal peptide, a fibronectin type II (FN II) domain, and two carbohydrate-recognition domains (CRDs) with special EPS and FND motifs. LvMR transcripts were mainly detected in the hepatopancreas, and presented a time-dependent response after pathogen challenge. The recombinant LvMR (rLvMR) could bind to various PAMPs and agglutinate microorganisms in a Ca²⁺-dependent manner with strong binding ability to _D-mannose and N-acetyl sugars. The knockdown of LvMR enhanced the expression of most NF-κB pathway genes, inflammation and redox genes, while it had no obvious effect on the transcription of most phagocytosis genes. Moreover, the knockdown of LvMR caused an increase in reactive oxygen species (ROS) content and inducible nitric oxide synthase (iNOS) activity in the hepatopancreas after Vibrio parahaemolyticus infection. All these results indicate that LvMR might perform as a PRR in immune recognition and a negative regulator of inflammation during bacterial infection. Full article

(This article belongs to the Special Issue New Insights into Molecular Innate Immunity)

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26 pages, 5678 KiB

Open AccessArticle

Novel Biomarkers for Inflammatory Bowel Disease and Colorectal Cancer: An Interplay between Metabolic Dysregulation and Excessive Inflammation

by Mohamed Salla, Jimmy Guo, Harshad Joshi, Marilyn Gordon, Hitesh Dooky, Justine Lai, Samantha Capicio, Heather Armstrong, Rosica Valcheva, Jason R. B. Dyck, Aducio Thiesen, Eytan Wine, Levinus A. Dieleman and Shairaz Baksh

Int. J. Mol. Sci. 2023, 24(6), 5967; https://doi.org/10.3390/ijms24065967 - 22 Mar 2023

Cited by 1 | Viewed by 2869

Abstract

Persistent inflammation can trigger altered epigenetic, inflammatory, and bioenergetic states. Inflammatory bowel disease (IBD) is an idiopathic disease characterized by chronic inflammation of the gastrointestinal tract, with evidence of subsequent metabolic syndrome disorder. Studies have demonstrated that as many as 42% of patients with ulcerative colitis (UC) who are found to have high-grade dysplasia, either already had colorectal cancer (CRC) or develop it within a short time. The presence of low-grade dysplasia is also predictive of CRC. Many signaling pathways are shared among IBD and CRC, including cell survival, cell proliferation, angiogenesis, and inflammatory signaling pathways. Current IBD therapeutics target a small subset of molecular drivers of IBD, with many focused on the inflammatory aspect of the pathways. Thus, there is a great need to identify biomarkers of both IBD and CRC, that can be predictive of therapeutic efficacy, disease severity, and predisposition to CRC. In this study, we explored the changes in biomarkers specific for inflammatory, metabolic, and proliferative pathways, to help determine the relevance to both IBD and CRC. Our analysis demonstrated, for the first time in IBD, the loss of the tumor suppressor protein Ras associated family protein 1A (RASSF1A), via epigenetic changes, the hyperactivation of the obligate kinase of the NOD2 pathogen recognition receptor (receptor interacting protein kinase 2 [RIPK2]), the loss of activation of the metabolic kinase, AMP activated protein kinase (AMPKα1), and, lastly, the activation of the transcription factor and kinase Yes associated protein (YAP) kinase, that is involved in proliferation of cells. The expression and activation status of these four elements are mirrored in IBD, CRC, and IBD-CRC patients and, importantly, in matched blood and biopsy samples. The latter would suggest that biomarker analysis can be performed non-invasively, to understand IBD and CRC, without the need for invasive and costly endoscopic analysis. This study, for the first time, illustrates the need to understand IBD or CRC beyond an inflammatory perspective and the value of therapeutics directed to reset altered proliferative and metabolic states within the colon. The use of such therapeutics may truly drive patients into remission. Full article

(This article belongs to the Special Issue New Insights into Molecular Innate Immunity)

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14 pages, 1983 KiB

Open AccessArticle

Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts

by Stephan A. Braun, Alexander T. Bauer, Csongor Németh, Annamária Rózsa, Louisa Rusch, Luise Erpenbeck, Sebastian Schloer, Steffi Silling, Dieter Metze, Peter A. Gerber, Stefan W. Schneider, Rolland Gyulai and Bernhard Homey

Int. J. Mol. Sci. 2022, 23(21), 13377; https://doi.org/10.3390/ijms232113377 - 02 Nov 2022

Cited by 2 | Viewed by 4772

Abstract

Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8/IL-8 expression in HPV-E6/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors. Full article

(This article belongs to the Special Issue New Insights into Molecular Innate Immunity)

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20 pages, 4642 KiB

Open AccessArticle

TXNIP Promotes Human NK Cell Development but Is Dispensable for NK Cell Functionality

by Eva Persyn, Sigrid Wahlen, Laura Kiekens, Sylvie Taveirne, Wouter Van Loocke, Els Van Ammel, Filip Van Nieuwerburgh, Tom Taghon, Bart Vandekerckhove, Pieter Van Vlierberghe and Georges Leclercq

Int. J. Mol. Sci. 2022, 23(19), 11345; https://doi.org/10.3390/ijms231911345 - 26 Sep 2022

Cited by 1 | Viewed by 1744

Abstract

The ability of natural killer (NK) cells to kill tumor cells without prior sensitization makes them a rising player in immunotherapy. Increased understanding of the development and functioning of NK cells will improve their clinical utilization. As opposed to murine NK cell development, human NK cell development is still less understood. Here, we studied the role of thioredoxin-interacting protein (TXNIP) in human NK cell differentiation by stable TXNIP knockdown or overexpression in cord blood hematopoietic stem cells, followed by in vitro NK cell differentiation. TXNIP overexpression only had marginal effects, indicating that endogenous TXNIP levels are sufficient in this process. TXNIP knockdown, however, reduced proliferation of early differentiation stages and greatly decreased NK cell numbers. Transcriptome analysis and experimental confirmation showed that reduced protein synthesis upon TXNIP knockdown likely caused this low proliferation. Contrary to its profound effects on the early differentiation stages, TXNIP knockdown led to limited alterations in NK cell phenotype, and it had no effect on NK cell cytotoxicity or cytokine production. Thus, TXNIP promotes human NK cell differentiation by affecting protein synthesis and proliferation of early NK cell differentiation stages, but it is redundant for functional NK cell maturation. Full article

(This article belongs to the Special Issue New Insights into Molecular Innate Immunity)

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Review

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29 pages, 2259 KiB

Open AccessReview

View from the Biological Property: Insight into the Functional Diversity and Complexity of the Gut Mucus

by Chengwei He, Han Gao, Shuzi Xin, Rongxuan Hua, Xueran Guo, Yimin Han, Hongwei Shang and Jingdong Xu

Int. J. Mol. Sci. 2023, 24(4), 4227; https://doi.org/10.3390/ijms24044227 - 20 Feb 2023

Cited by 1 | Viewed by 3895

Abstract

Due to mucin’s important protective effect on epithelial tissue, it has garnered extensive attention. The role played by mucus in the digestive tract is undeniable. On the one hand, mucus forms “biofilm” structures that insulate harmful substances from direct contact with epithelial cells. On the other hand, a variety of immune molecules in mucus play a crucial role in the immune regulation of the digestive tract. Due to the enormous number of microorganisms in the gut, the biological properties of mucus and its protective actions are more complicated. Numerous pieces of research have hinted that the aberrant expression of intestinal mucus is closely related to impaired intestinal function. Therefore, this purposeful review aims to provide the highlights of the biological characteristics and functional categorization of mucus synthesis and secretion. In addition, we highlight a variety of the regulatory factors for mucus. Most importantly, we also summarize some of the changes and possible molecular mechanisms of mucus during certain disease processes. All these are beneficial to clinical practice, diagnosis, and treatment and can provide some potential theoretical bases. Admittedly, there are still some deficiencies or contradictory results in the current research on mucus, but none of this diminishes the importance of mucus in protective impacts. Full article

(This article belongs to the Special Issue New Insights into Molecular Innate Immunity)

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24 pages, 521 KiB

Open AccessReview

Effects of SARS-CoV-2 Inflammation on Selected Organ Systems of the Human Body

by Marta Kopańska, Edyta Barnaś, Joanna Błajda, Barbara Kuduk, Anna Łagowska and Agnieszka Banaś-Ząbczyk

Int. J. Mol. Sci. 2022, 23(8), 4178; https://doi.org/10.3390/ijms23084178 - 10 Apr 2022

Cited by 11 | Viewed by 2754

Abstract

Introduction and purpose of the study: SARS-CoV-2 virus does not only affect the respiratory system. It may cause damage to many organ systems with long-term effects. The latest scientific reports inform that this virus leaves a long-term trace in the nervous, circulatory, respiratory, urinary and reproductive systems. It manifests itself in disturbances in the functioning of the organs of these systems, causing serious health problems. The aim of the study was to review the latest research into the long-term effects of COVID-19 and determine how common these symptoms are and who is most at risk. Based on a literature review using the electronic scientific databases of PubMed and Web of Science on the long-term effects of SARS-CoV-2 infection, 88 studies were included in the analysis. The information contained in the analyzed literature shows that the SARS-CoV-2 virus can cause multi-organ damage, causing a number of long-term negative health complications. Conclusions: There is evidence that the virus can cause long-term complications lasting more than six months. They mainly concern disturbances in the functioning of the nervous, circulatory and respiratory systems. However, these studies are small or short-lasting, and many are speculative. Full article

(This article belongs to the Special Issue New Insights into Molecular Innate Immunity)

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Other

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13 pages, 1692 KiB

Open AccessBrief Report

Regulatory T-Cell Enhancement, Expression of Adhesion Molecules, and Production of Anti-Inflammatory Factors Are Differentially Modulated by Spheroid-Cultured Mesenchymal Stem Cells

by Amandda Évelin Silva-Carvalho, Ingrid Gracielle Martins da Silva, José Raimundo Corrêa and Felipe Saldanha-Araujo

Int. J. Mol. Sci. 2022, 23(22), 14349; https://doi.org/10.3390/ijms232214349 - 18 Nov 2022

Cited by 1 | Viewed by 1400

Abstract

The culture of mesenchymal stem cells (MSCs) as spheroids promotes a more physiological cellular behavior, as it more accurately reflects the biological microenvironment. Nevertheless, mixed results have been found regarding the immunosuppressive properties of spheroid-cultured MSCs (3D-MSCs), the mechanisms of immunoregulation of 3D-MSCs being scarcely described at this point. In the present study, we constructed spheroids from MSCs and compared their immunosuppressive potential with that of MSCs cultured in monolayer (2D-MSCs). First, we evaluated the ability of 2D-MSCs and 3D-MSCs to control the activation and proliferation of T-cells. Next, we evaluated the percentage of regulatory T-cells (Tregs) after the co-culturing of peripheral blood mononuclear cells (PBMCs) with 2D-MSCs and 3D-MSCs. Finally, we investigated the expression of adhesion molecules, as well as the expressions of several anti-inflammatory transcripts in 2D-MSCs and 3D-MSCs maintained in both inflammatory and non-inflammatory conditions. Interestingly, our data show that several anti-inflammatory genes are up-regulated in 3D-MSCs, and that these cells can control T-cell proliferation. Nevertheless, 2D-MSCs are more efficient in suppressing the immune cell proliferation. Importantly, contrary to what was observed in 3D-MSCs, the expressions of ICAM-1 and VCAM-1 are significantly upregulated in 2D-MSCs exposed to an inflammatory environment. Furthermore, only 2D-MSCs are able to promote the enhancement of Tregs. Taken together, our data clearly show that the immunosuppressive potential of MSCs is significantly impacted by their shape, and highlights the important role of cell–cell adhesion molecules for optimal MSC immunomodulatory function. Full article

(This article belongs to the Special Issue New Insights into Molecular Innate Immunity)

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