Dysfunction of Anti-inflammatory Macrophages in Chronic Intestinal Inflammation

The connection between inflammation and cancer is well-established and supported by genetic, pharmacological and epidemiological data. The inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis, have been described as important promoters for colorectal cancer development. Risk factors include environmental and food-borne mutagens, dysbalance of intestinal microbiome composition and chronic intestinal inflammation, with loss of intestinal epithelial barrier and enhanced cell proliferation rate. Therapies aimed at shutting down mucosal inflammatory response represent the foundation for IBDs treatment. However, when applied for long periods, they can alter the immune system and promote microbiome dysbiosis and carcinogenesis. Therefore, it is imperative to find new safe substances acting as both potent anti-inflammatory and anti-pathogen agents. Lactoferrin (Lf), an iron-binding glycoprotein essential in innate immunity, is generally recognized as safe and used as food supplement due to its multifunctionality. Lf possesses a wide range of immunomodulatory and anti-inflammatory properties against different aseptic and septic inflammatory pathologies, including IBDs. Moreover, Lf exerts anti-adhesive, anti-invasive and anti-survival activities against several microbial pathogens that colonize intestinal mucosa of IBDs patients. This review focuses on those activities of Lf potentially useful for the prevention/treatment of intestinal inflammatory pathologies associated with colorectal cancer development.

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Anti-inflammatory role of sympathetic nerves in chronic intestinal inflammation

Gut ◽

10.1136/gut.2007.125401 ◽

2008 ◽

Vol 57 (7) ◽

pp. 911-921 ◽

Cited By ~ 96

Author(s):

R H Straub ◽

F Grum ◽

U Strauch ◽

S Capellino ◽

F Bataille ◽

...

Keyword(s):

Intestinal Inflammation ◽

Sympathetic Nerves ◽

Anti Inflammatory ◽

Chronic Intestinal Inflammation

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Enteric glial cells favour accumulation of anti-inflammatory macrophages during the resolution of muscularis inflammation

10.1101/2021.06.10.447700 ◽

2021 ◽

Author(s):

Michelle Stakenborg ◽

Saeed Abdurahiman ◽

Veronica De Simone ◽

Gera Goverse ◽

Nathalie Stakenborg ◽

...

Keyword(s):

Glial Cells ◽

Intestinal Inflammation ◽

Mononuclear Phagocyte ◽

Inflammatory Factors ◽

Monocyte Differentiation ◽

Enteric Glial Cells ◽

Monocyte Recruitment ◽

Microenvironmental Factors ◽

Anti Inflammatory ◽

Inflammatory Macrophages

Objective: Monocyte-derived macrophages (Mϕs) are crucial regulators during muscularis inflammation. However, it is unclear which microenvironmental factors are responsible for monocyte recruitment and neurotrophic Mϕ differentiation in this paradigm. Here, we investigate Mϕ heterogeneity at different stages of muscularis inflammation and determine how environmental cues can attract and activate tissue protective Mϕs. Design: Single cell RNA sequencing was performed on immune cells from the muscularis of wild-type and CCR2-/- mice at different timepoints after muscularis inflammation. CX3CR1GFP/+ and CX3CR1CreERT2 R26YFP mice were analyzed by flow cytometry and immunofluorescence. The transcriptome of enteric glial cells (EGCs) was investigated using PLPCreERT2 Rpl22HA mice. In addition, we assessed the effect of supernatant from neurosphere-derived EGCs on monocyte differentiation based on the expression of pro- and anti-inflammatory factors. Results: Muscularis inflammation induced marked alterations in mononuclear phagocyte populations associated with a rapid infiltration of Ly6c+ monocytes that locally acquired unique transcriptional states. Trajectory inference analysis revealed two main pro-resolving Mϕs subpopulations during the resolution of muscularis inflammation, i.e. Cd206+ MhcIIhi and Timp2+ MhcIIlo Mϕs, which were both derived from CCR2+ monocytes. Interestingly, we found that EGCs were able to sense damage to the muscularis to stimulate monocyte recruitment and differentiation towards pro-resolving Mϕs via CCL2 and CSF1, respectively. Conclusion: Our study provides a comprehensive insight into pro-resolving Mϕ differentiation and their regulators during muscularis inflammation. We deepened our understanding in the interaction between EGCs and Mϕs, thereby highlighting pro-resolving Mϕ differentiation as a potential novel therapeutic strategy for the treatment of intestinal inflammation.

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P315 Short-chain fatty acid profile in inflammatory bowel disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.444 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S311-S312

Author(s):

L Oliveira ◽

L Yukie Sassaki ◽

A Elisa Valencise Quagli ◽

J Ribeiro de Barros

Keyword(s):

Fatty Acid ◽

Intestinal Inflammation ◽

Nutrient Deficiency ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Bacterial Degradation ◽

Inflammatory Bowel ◽

Anti Inflammatory ◽

And Control ◽

Chronic Intestinal Inflammation

Abstract Background Short-chain fatty acids (SCFAs) are products of colonic bacterial degradation of dietary fibre. They are important in the colon, affecting the morphology and function of colonocytes. SCFAs consist of a molecule with one to six carbons, of which acetate, propionate and butyrate are the most abundant. In recent decades, it has become apparent that SCFAs can play a key role in the prevention and treatment of metabolic syndrome, intestinal disorders and certain cancers. Crohn’s disease (CD) and ulcerative colitis (UC) are characterised by recurrent chronic intestinal inflammation, probably due to an inadequate immune response coupled with intestinal microbiota imbalance. The aim of this study was to evaluate the profile of SCFA in patients with UC and CD, and compared with non-ill individuals. Methods The individuals were divided into three groups: RCU, CD and control, the faeces were donated by them, and the SCFAs were measured by chromatographic analysis using a Thermo Scientific GC-MS coupled to a Thermo ISQ 230ST mass detector. All results are expressed as mean ± SEM. Results It was possible to observe a different SCFAs profile between individuals with CD and UC and control where acetate and propionate levels in patients with UC and CD were higher than in non-sick individuals and butyrate with lower levels in individuals with CD and RCU (Graph 1). SCFAs have anti-inflammatory capabilities and also a preferred energy source for colon epithelial cells, as well as lowering the pH of the colon and inhibiting the growth of pathogenic organisms. Dysbiosis decreases butyrate concentrations, which may result in nutrient deficiency at the epithelial level, altering immune responses, as well as acting directly as an anti-inflammatory agent by disabling the NFκB pathway, with a consequent decrease in inflammatory cytokine synthesis. Conclusion Thus, the reported results have implications for various physiological and pathological conditions in inflammatory bowel diseases, especially with respect to butyrate and the production of inflammatory mediators, and partly explain the beneficial effects attributed to this fatty acid in the treatment of inflammatory and inflammatory diseases support the realisation of new studies aimed at the development of therapeutic alternatives to the use of conventional anti-inflammatory drugs.

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Idebenone Protects against Spontaneous Chronic Murine Colitis by Alleviating Endoplasmic Reticulum Stress and Inflammatory Response

Biomedicines ◽

10.3390/biomedicines8100384 ◽

2020 ◽

Vol 8 (10) ◽

pp. 384 ◽

Cited By ~ 1

Author(s):

Sonia Shastri ◽

Tanvi Shinde ◽

Agampodi Promoda Perera ◽

Nuri Gueven ◽

Rajaraman Eri

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Intestinal Inflammation ◽

Activity Index ◽

Goblet Cells ◽

Inflammatory Activity ◽

Mrna Levels ◽

Anti Inflammatory ◽

The Impact ◽

Chronic Intestinal Inflammation

Endoplasmic reticulum (ER) stress in intestinal secretory goblet cells has been linked to the development of ulcerative colitis (UC). Emerging evidence suggests that the short chain quinone drug idebenone displays anti-inflammatory activity in addition to its potent antioxidant and mitochondrial electron donor properties. This study evaluated the impact of idebenone in Winnie mice, that are characterized by spontaneous chronic intestinal inflammation and ER stress caused by a missense mutation in the mucin MUC2 gene. Idebenone (200 mg/kg) was orally administered daily to 5–6 weeks old Winnie mice over a period of 21 days. Idebenone treatment substantially improved body weight gain, disease activity index (DAI), colon length and histopathology score. Immunohistochemistry revealed increased expression of MUC2 protein in goblet cells, consistent with increased MUC2 mRNA levels. Furthermore, idebenone significantly reduced the expression of the ER stress markers C/EBP homologous protein (CHOP), activating transcription factor 6 (ATF6) and X-box binding protein-1 (XBP-1) at both mRNA and protein levels. Idebenone also effectively reduced pro-inflammatory cytokine levels in colonic explants. Taken together, these results indicate that idebenone could represent a potential therapeutic approach against human UC by its strong anti-inflammatory activity and its ability to reduce markers of ER stress.

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P104 Anaeroplasma, a potential anti-inflammatory probiotic for the treatment of chronic intestinal inflammation

10.1136/annrheumdis-2018-ewrr2019.92 ◽

2019 ◽

Cited By ~ 3

Author(s):

A Beller ◽

A Kruglov ◽

P Durek ◽

V von Goetze ◽

U Hoffmann ◽

...

Keyword(s):

Intestinal Inflammation ◽

Anti Inflammatory ◽

Chronic Intestinal Inflammation

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Anti-Inflammatory and Antiapoptotic Responses to Infection: A Common Denominator of Human and Bovine Macrophages Infected withMycobacterium aviumSubsp.paratuberculosis

BioMed Research International ◽

10.1155/2013/908348 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 19

Author(s):

Naiara Abendaño ◽

Ramon A. Juste ◽

Marta Alonso-Hearn

Keyword(s):

Molecular Mechanisms ◽

Mononuclear Cells ◽

Intestinal Inflammation ◽

Common Denominator ◽

Bacterial Survival ◽

Peripheral Blood Mononuclear ◽

Susceptible Host ◽

Human Macrophages ◽

Anti Inflammatory ◽

Chronic Intestinal Inflammation

Mycobacterium aviumsubsp.paratuberculosis(Map) is the causative agent of a chronic intestinal inflammation in ruminants named Johne's disease or paratuberculosis and a possible etiopathological agent of human Crohn's disease (CD). Analysis of macrophage transcriptomes in response toMapinfection is expected to provide key missing information in the understanding of the role of this pathogen in establishing an inappropriate and persistent infection in a susceptible host and of the molecular mechanisms that might underlie the early phases of CD. In this paper we summarize transcriptomic studies of human and bovine peripheral blood mononuclear cells (PBMC), monocyte-derived macrophages (MDMs), and macrophages-like cell linesin vitroinfected withMap. Most studies included in this paper consistently reported common gene expression signatures of bovine and human macrophages in response toMapsuch as enhanced expression of the anti-inflammatory cytokines IL-10 and IL-6, which promote bacterial survival. Overexpression of IL-10 could be responsible for theMap-associated reduction in the expression of the proapoptotic TNF-αgene observed in bovine and human macrophages.

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The Potential of Food Protein-Derived Bioactive Peptides against Chronic Intestinal Inflammation

Mediators of Inflammation ◽

10.1155/2020/6817156 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Wanying Zhu ◽

Liying Ren ◽

Li Zhang ◽

Qinqin Qiao ◽

Muhammad Zahid Farooq ◽

...

Keyword(s):

Bioactive Peptides ◽

Intestinal Inflammation ◽

Janus Kinase ◽

Mitogen Activated Protein Kinase ◽

Inflammatory Activity ◽

Peptide Transporter ◽

Food Protein ◽

Anti Inflammatory ◽

Chronic Intestinal Inflammation

Inflammation can cause various chronic diseases like inflammatory bowel diseases. Various food protein-derived bioactive peptides (BAPs) with anti-inflammatory activity have the potential to manage these diseases. The aim of this paper is to overview the mechanisms and the molecular targets of BAPs to exert anti-inflammatory activity. In this review, the in vitro and in vivo effects of BAPs on intestinal inflammation are highlighted. The mechanism, pathways, and future perspectives of BAPs as the potential sources of therapeutic treatments to alleviate intestinal inflammation are provided, including nuclear factor-κB, mitogen-activated protein kinase, Janus kinase-signal transducer and activator of transcription, and peptide transporter 1 (PepT1), finding that PepT1 and gut microbiota are the promising targets for BAPs to alleviate the intestinal inflammation. This review provides a comprehensive understanding of the role of dietary BAPs in attenuating inflammation and gives a novel direction in nutraceuticals for people or animals with intestinal inflammation.

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Cell-intrinsic IL4R alpha independence of large intestinal RELMα+ Ym1+ macrophages

10.1101/2020.12.17.423033 ◽

2020 ◽

Author(s):

Ruth Forman ◽

Larisa Logunova ◽

Hannah Smith ◽

Kelly Wemyss ◽

Iris Mair ◽

...

Keyword(s):

Large Intestine ◽

Post Infection ◽

Macrophage Activation ◽

Intestinal Inflammation ◽

Infection Model ◽

Unexpected Finding ◽

Trichuris Muris ◽

Anti Inflammatory ◽

Inflammatory Macrophages

ABSTRACTThe balance of pro-inflammatory and anti-inflammatory macrophages is critically important in enabling the development and resolution of inflammatory responses. Anti-inflammatory macrophages have been shown to be activated by IL4 and/or IL13 via the IL4Rα. In the context of type 2 immunity, anti-inflammatory macrophages have been defined by the expression of the signature markers RELMα, CD206 and Ym1, associated with activation of macrophages via the IL4Rα. Despite a breadth of inflammatory pathologies associated with the large intestine, many of which feature unbalanced macrophage activation states, little is known about how large intestinal macrophages are activated. Here, we address this important knowledge gap by using a Trichuris muris infection model of resolving type 2 intestinal inflammation, in combination with transgenic mice (IL4Rαfl/fl.CX3CR1Cre) and IL4Rα-deficient/wild-type mixed bone marrow chimaeras. These models allowed us to interrogate the role of IL4/IL13 in macrophage activation driven by inflammation of the large intestine. We make the unexpected finding that education of large intestinal macrophages towards a RELMα and Ym1 expressing cell type during type 2 inflammation, does not require IL4Rα expression on macrophages. Thus, upregulation of RELMα and Ym1 post infection is independent of macrophage IL4Rα expression. Further, this independence is maintained even when the mice are treated with anti-IFNγ antibody to create a strongly polarised Th2 environment. In contrast to RELMα and Ym1, PD-L2 expression on macrophages post infection was dependent on IL4Rα signalling in the macrophages. These data challenge existing paradigms, evidencing that expression of RELMα and Ym1 by macrophages, typically regarded as having anti-inflammatory functions, do not always rely on IL4/IL13.

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