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Host Defence Peptides: Modulation of Inflammation in Health and Disease

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A special issue of Vaccines (ISSN 2076-393X).

Deadline for manuscript submissions: closed (30 June 2018) | Viewed by 38340

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Special Issue Editor

Dr. Neeloffer Mookherjee

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Guest Editor

Manitoba Center for Proteomics and Systems Biology, Department of Internal Medicine & Immunology, University of Manitoba, Winnipeg, MB, Canada
Interests: immunomodulation and inflammation: understanding molecular processes that underlie chronic inflammation; delineating the immunomodulatory functions of host defence peptides in chronic inflammatory diseases, such as arthritis and asthma; development of immunomodulatory therapies using synthetic peptides for the control of inflammatory diseases
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Special Issue Information

Dear Colleagues,

This Special Issue of Vaccines is focused on the immunomodulatory functions of Host Defence Peptides (HDPs). Contributions to this issue are expected to encompass basic and translation research on aspects of how HDPs influence inflammation in health and disease. HDPs, also known as antimicrobial peptides, are cationic, typically amphipathic, short peptides, expressed across diverse species that include microbes, insects, amphibians, reptiles, plants and mammals. The most well-characterized HDPs in mammals are cathelicidins and defensins. HDPs are important in host defence mechanisms required for resolution of infections and modulation of inflammation. Studies in the last three decades have established that HDPs exert a wide range of functions that influence immune responses. HDPs are essential elements of innate immunity and play an integral role in the initiation, polarisation and enhancement of adaptive immune response. Immunity-related functions of HDPs influence immune homeostasis, wound healing and various aspects of the inflammatory process. It is, thus, not surprising that altered expression of HDPs have been associated with various chronic inflammatory diseases and autoimmunity. However, the role of HDPs in chronic inflammatory and autoimmune disease is not fully elucidated. Studies have demonstrated that HDPs contribute to both immune activation and regulation of inflammation, which are dependent on cellular composition, environmental stimuli and the kinetics of inflammatory response. In this Special Issue, we seek to provide insights into the complexity of mechanisms that underlie diverse immunomodulatory functions of HDPs. We also aim to include research on HDPs in chronic inflammatory disease and autoimmunity, and the application of HDPs and/or related peptides as novel immunomodulatory therapeutics.

Dr. Neeloffer Mookherjee
Guest Editor

Manuscript Submission Information

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Keywords

Inflammation
Immunomodulation
Immune homeostasis
Chronic inflammatory disease
Autoimmunity
Innate immunity
Antimicrobial peptides
Immunomodulatory therapy

Published Papers (7 papers)

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Research

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18 pages, 5434 KiB

Open AccessArticle

Catestatin Regulates Epithelial Cell Dynamics to Improve Intestinal Inflammation

by Nour Eissa, Hayam Hussein, Ruth Mesgna, Sandra Bonin, Geoffrey N. Hendy, Marie-Hélène Metz-Boutigue, Charles N. Bernstein and Jean-Eric Ghia

Vaccines 2018, 6(4), 67; https://doi.org/10.3390/vaccines6040067 - 20 Sep 2018

Cited by 23 | Viewed by 5108

Abstract

Ulcerative colitis (UC) is characterized by aberrant regulation of tight junctions (TJ), signal transducer and activator of transcription 3 (STAT3), and interleukin (IL)-8/18, which lead to intestinal barrier defects. Catestatin (CST), an enterochromaffin-derived peptide, regulates immune communication and STAT-3 in the inflamed intestine. Here, we investigated the effects of CST during the development of inflammation using human biopsies from patients with active UC, human colonic epithelial cells (Caco2), and an experimental model of UC (dextran sulfate sodium [DSS]-colitis). In UC patients, the protein and mRNA level of CST was significantly decreased. Colonic expression of CST showed a strong positive linear relationship with TJ proteins and STAT3, and a strong negative correlation with IL-8 and IL-18. Intra-rectal administration of CST reduced the severity of experimental colitis, IL-18 colonic levels, maintained TJ proteins and enhanced the phosphorylation of STAT3. CST administration increased proliferation, viability, migration, TJ proteins, and p-STAT3 levels, and reduced IL-8 & IL-18 in LPS- & DSS-induced Caco2 cell epithelial injury, and the presence of STAT-3 inhibitor abolished the beneficial effect of CST. In inflammatory conditions, we conclude that CST could regulate intestinal mucosal dynamic via a potential STAT3-dependent pathway that needs to be further defined. Targeting CST in intestinal epithelial cells (IECs) should be a promising therapeutic approach such as when intestinal epithelial cell homeostasis is compromised in UC patients. Full article

(This article belongs to the Special Issue Host Defence Peptides: Modulation of Inflammation in Health and Disease)

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15 pages, 2886 KiB

Open AccessArticle

β-Defensins Coordinate In Vivo to Inhibit Bacterial Infections of the Trachea

by Lisa Kathleen Ryan, Jichuan Wu, Kyell Schwartz, Sunghan Yim and Gill Diamond

Vaccines 2018, 6(3), 57; https://doi.org/10.3390/vaccines6030057 - 28 Aug 2018

Cited by 11 | Viewed by 3846

Abstract

β-defensins are predicted to play an important role in innate immunity against bacterial infections in the airway. We previously observed that a type III-secretion product of Bordetella bronchiseptica inhibits the NF-κB-mediated induction of a β-defensin in airway epithelial cells in vitro. To confirm this in vivo and to examine the relative roles of other β-defensins in the airway, we infected wild-type C57BL/6 mice and mice with a deletion of the mBD-1 gene with B. bronchiseptica wild-type strain, RB50 and its mutant strain lacking the type III-secretion system, WD3. The bacteria were quantified in the trachea and the nasal tissue and mRNA levels of mouse β-defensin-3 (mBD-3) were assessed after 24 h. Infection with the wild-type bacterial strain resulted in lower mBD-3 mRNA levels in the trachea than in mice infected with the type III-deficient strain. Furthermore, we observed an increase in bacterial numbers of RB50 only in the tracheas of mBD-1-deficient mice. Neutrophils were also more abundant on the trachea in RB50 infected WT mice but not in the bronchiolar lavage fluid (BAL), compared with WD3 infected WT and mBD-1^−/− mice, indicating that the coordination of β-defensin chemotactic effects may be confined to tracheal epithelial cells (TEC). RB50 decreased the ability of mice to mount an early specific antibody response, seven days after infection in both WT and mBD-1^−/− mice but there were no differences in titers between RB50-infected WT and mBD-1^−/− mice or between WD3-infected WT and mBD-1^−/− mice, indicating mBD-1 was not involved in induction of the humoral immune response to the B. bronchiseptica. Challenge of primary mouse TEC in vitro with RB50 and WD3, along with IL-1β, further corroborated the in vivo studies. The results demonstrate that at least two β-defensins can coordinate early in an infection to limit the growth of bacteria in the trachea. Full article

(This article belongs to the Special Issue Host Defence Peptides: Modulation of Inflammation in Health and Disease)

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13 pages, 2430 KiB

Open AccessArticle

Cytokines IL-17, TNF and IFN-γ Alter the Expression of Antimicrobial Peptides and Proteins Disparately: A Targeted Proteomics Analysis using SOMAscan Technology

by Anthony Altieri, Hadeesha Piyadasa, Breann Recksiedler, Victor Spicer and Neeloffer Mookherjee

Vaccines 2018, 6(3), 51; https://doi.org/10.3390/vaccines6030051 - 07 Aug 2018

Cited by 12 | Viewed by 4708

Abstract

Antimicrobial peptides, also known as host defence peptides, are immunomodulatory molecules required to resolve infections. Antimicrobial peptides and proteins (APPs) are important in the control of infections in the lungs. Despite evidence that APPs exhibit a wide range of immune functions and modulate inflammation, the effect of inflammatory cytokines on the expression of APPs is not completely defined. In this study, we profiled the expression of 39 different APPs in human bronchial epithelial cells (HBEC) using Slow Off-rate Modified Aptamer (SOMAmer)-based protein array, in the presence and absence of three different inflammatory cytokines (IL-17, TNF and IFN-γ). Expression of 13 different APPs was altered in response to IL-17, TNF or IFN-γ. Independent validations of selected proteins from the proteomics screen i.e., those that were significantly enhanced by >2-fold change (p < 0.01) using western blots conclusively demonstrated that inflammatory cytokines alter the expression of APPs differentially. For example, the abundance of cathepsin S was enhanced by only IFN-γ, whereas lipocalin-2 was increased by IL-17 alone. Abundance of elafin increased in presence of IL-17 or TNF, but decreased in response to IFN-γ. Whereas the abundance of cathepsin V decreased following stimulation with IL-17, TNF and IFN-γ. The results of this study demonstrate that inflammatory cytokines alter the expression of APPs disparately. This suggests that the composition of the inflammatory cytokine milieu may influence APPs abundance and thus alter the processes required for infection control and regulation of inflammation in the lungs. Full article

(This article belongs to the Special Issue Host Defence Peptides: Modulation of Inflammation in Health and Disease)

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11 pages, 1315 KiB

Open AccessArticle

Effects of LL-37 on Gingival Fibroblasts: A Role in Periodontal Tissue Remodeling?

by Maelíosa T. C. McCrudden, Katherine O’Donnell, Chris R. Irwin and Fionnuala T. Lundy

Vaccines 2018, 6(3), 44; https://doi.org/10.3390/vaccines6030044 - 23 Jul 2018

Cited by 11 | Viewed by 4380

Abstract

Mounting evidence suggests that the host defence peptide, LL-37, plays a role in both inflammation and in wound healing; however, the role of this peptide in the remodeling and maintenance of oral tissues is not yet fully understood. Fibroblasts are the most abundant cell type within the periodontal tissues, and gingival fibroblasts play an important role in maintaining and repairing the gingival tissues which are constantly exposed to external insults. In this study we examined the direct effects of LL-37 treatment on gingival fibroblasts and found that LL-37 significantly increased secretion of both interleukin 8 (IL-8) and IL-6 from these cells. LL-37 tended to decrease matrix metalloproteinase (MMP) activity in gingival fibroblasts, but this decrease did not reach statistical significance. LL-37 significantly increased tissue inhibitor of metalloproteinase-1 (TIMP-1) production by gingival fibroblasts, but had no significant effect on TIMP-2 levels. LL-37 was also shown to significantly increase production of basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and keratinocyte growth factor (KGF) in gingival fibroblasts. Taken together, these results suggest an important role for the host defence peptide, LL-37, in modulating the fibroblast response to remodeling in periodontal tissues. Full article

(This article belongs to the Special Issue Host Defence Peptides: Modulation of Inflammation in Health and Disease)

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Review

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19 pages, 1288 KiB

Open AccessReview

The Immunomodulatory and Antimicrobial Properties of the Vertebrate Ribonuclease A Superfamily

by Laura Schwartz, Ariel Cohen, Jason Thomas and John David Spencer

Vaccines 2018, 6(4), 76; https://doi.org/10.3390/vaccines6040076 - 20 Nov 2018

Cited by 24 | Viewed by 3979

Abstract

The Ribonuclease A Superfamily is composed of cationic peptides that are secreted by immune cells and epithelial tissues. Although their physiological roles are unclear, several members of the vertebrate Ribonuclease A Superfamily demonstrate antimicrobial and immune modulation activities. The objective of this review is to provide an overview of the published literature on the Ribonuclease A Superfamily with an emphasis on each peptide’s regulation, antimicrobial properties, and immunomodulatory functions. As additional insights emerge regarding the mechanisms in which these ribonucleases eradicate invading pathogens and modulate immune function, these ribonucleases may have the potential to be developed as a novel class of therapeutics for some human diseases. Full article

(This article belongs to the Special Issue Host Defence Peptides: Modulation of Inflammation in Health and Disease)

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23 pages, 2461 KiB

Open AccessReview

Cathelicidins: Immunomodulatory Antimicrobials

by Roel M. Van Harten, Esther Van Woudenbergh, Albert Van Dijk and Henk P. Haagsman

Vaccines 2018, 6(3), 63; https://doi.org/10.3390/vaccines6030063 - 14 Sep 2018

Cited by 146 | Viewed by 10823

Abstract

Cathelicidins are host defense peptides with antimicrobial and immunomodulatory functions. These effector molecules of the innate immune system of many vertebrates are diverse in their amino acid sequence but share physicochemical characteristics like positive charge and amphipathicity. Besides being antimicrobial, cathelicidins have a wide variety in immunomodulatory functions, both boosting and inhibiting inflammation, directing chemotaxis, and effecting cell differentiation, primarily towards type 1 immune responses. In this review, we will examine the biology and various functions of cathelicidins, focusing on putting in vitro results in the context of in vivo situations. The pro-inflammatory and anti-inflammatory functions are highlighted, as well both direct and indirect effects on chemotaxis and cell differentiation. Additionally, we will discuss the potential and limitations of using cathelicidins as immunomodulatory or antimicrobial drugs. Full article

(This article belongs to the Special Issue Host Defence Peptides: Modulation of Inflammation in Health and Disease)

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17 pages, 534 KiB

Open AccessReview

Contribution of Host Defence Proteins and Peptides to Host-Microbiota Interactions in Chronic Inflammatory Lung Diseases

by Anne M. Van der Does, Gimano D. Amatngalim, Bart Keijser, Pieter S. Hiemstra and Remi Villenave

Vaccines 2018, 6(3), 49; https://doi.org/10.3390/vaccines6030049 - 28 Jul 2018

Cited by 7 | Viewed by 4794

Abstract

The respiratory tract harbours a variety of microorganisms, collectively called the respiratory microbiota. Over the past few years, alterations in respiratory and gut microbiota composition have been associated with chronic inflammatory diseases of the lungs. How these changes influence disease development and progression is an active field of investigation. Identifying and understanding host-microbiota interactions and factors contributing to these interactions could promote the development of novel therapeutic strategies aimed at restoring host-microbiota homeostasis. In this review, we discuss recent literature on host-microbiota interactions in the respiratory tract, with a specific focus on the influence of endogenous host defence peptides and proteins (HDPs) on the composition of microbiota populations in vivo and explore possible HDPs-related therapeutic approaches targeting microbiota dysbiosis in chronic inflammatory lung diseases. Full article

(This article belongs to the Special Issue Host Defence Peptides: Modulation of Inflammation in Health and Disease)

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