Role of Eosinophils in Intestinal Inflammation and Fibrosis in Inflammatory Bowel Disease: An Overlooked Villain?

Jacobs, Inge; Ceulemans, Michael; Wauters, Lucas; Breynaert, Christine; Vermeire, Séverine; Verstockt, Bram; Vanuytsel, Tim

doi:10.3389/fimmu.2021.754413

Cited by 37 publications

(63 citation statements)

References 220 publications

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“…It is known that eosinophils prevent auto-inflammatory disorders on the mucosal surfaces, such as inflammatory bowel syndrome in the guts 25,26 by secreting Interleukin-1 receptor antagonist (IL1RA) 27-29 , Program death ligand 1 (PD-L1) 17,22 , and Indoleamine 2,3-dioxygenase (IDO) 13,30 . Based on the differences identified in the cytokine profile, we hypothesized that RB50 might promote the expression of one of these molecules, to suppress the secretion of IL17 by eosinophils.…”

Section: Resultsmentioning

confidence: 99%

BordetellaSpp. Utilize T3SS To Promote Secretion of IL1RA Leading to Long-Term Persistent Infections

Williams

Roan

First

et al. 2022

Preprint

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A common feature of pathogens is their ability to suppress host immune responses. Understanding the molecular mechanisms and the common pathways that bacteria utilize to block host immune signaling cascade might provide novel avenues for vaccine and therapeutic development. Preventable infectious diseases remain one of the major causes of morbidity and mortality worldwide and the current rise in antibiotic resistance is increasing this burden. Bordetella spp. are respiratory pathogens that cause the long-term illness known as whoop-ing cough. Bordetella infections cause over 150,000 deaths each year, despite a vaccine be-ing available. In our studies, we used the mouse pathogen B. bronchiseptica to investigate the pneumonic stage of disease, which very well mimics the fatal disease caused by B. pertussis. In our previous work we discovered a B. bronchiseptica mutant, RB50DbtrS, that clears rapidly from the lungs of mice and generates protective immunity that lasts for at least 15 months post-challenge. Combining the mouse immunological tools and both bacteria, the wildtype RB50 and mutant RB50DbtrS, which persists for up to 56 days and clears in 14-21 days, respectively, we investigated the mechanisms by which the wildtype B. bronchiseptica blocks host immune response to cause long term lung infection. Previous research indicated eosinophils as critical for rapid clearance of the mutant bacteria from the lungs. In vitro assays with eosinophils demonstrated that the RB50DbtrS mutant strain promotes the secretion of pro-inflammatory signals. In contrast, infection of eosinophils with RB50 promoted the se-cretion of anti-inflammatory signals such as IL1RA. Interestingly, IL1RA was also increased in the lungs of mice infected with the wildtype but not with the mutant RB50 strain. Infection with RB50DbscN, which lacks a functional type 3 secretion system (T3SS), was sufficient to prevent IL1RA induction suggesting that the bacterial effector responsible for IL1RA upregula-tion is a substrate of the T3SS. Supplementation with IL1RA after infection with RB50 or RB50DbtrS resulted in increased lung bacterial burden for both bacterial strains. However, more rapid clearance of RB50 was observed after infection of mice in which IL1RA was knocked out. Furthermore, anti-IL1RA antibody treatment promoted rapid clearance of not only RB50 but also the human pathogens B. pertussis and B. parapertussis. This suggests that IL1RA may be a promising therapeutic target to treat severe cases of whooping cough. Overall, this work demonstrates that Bordetella spp. induces IL1RA expression to promote persistence using the T3SS. Since other bacteria have also been shown to target IL1RA, this may be a conserved bacterial mechanism to promote host-immune suppression.

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Section: Resultsmentioning

confidence: 99%

BordetellaSpp. Utilize T3SS To Promote Secretion of IL1RA Leading to Long-Term Persistent Infections

Williams

Roan

First

et al. 2022

Preprint

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“…This pattern was strongly associated with higher levels of plasma CCL11, but with lower levels of plasma IL12B. CCL11, also known as eotaxin-1, is a selective chemoattractant for eosinophils, mediating the activation and recruitment of these cells to the intestinal lamina propria [37,38]. Circulating CCL11 levels have been shown to be elevated in patients with IBD and are associated with inflammatory disease activity [3,39].…”

Section: Discussionmentioning

confidence: 99%

Long-Term Dietary Patterns Are Reflected in the Plasma Inflammatory Proteome of Patients with Inflammatory Bowel Disease

Bourgonje

Bolte²,

Vranckx³

et al. 2022

Nutrients

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Diet plays an important role in the development and progression of inflammatory bowel disease (IBD, comprising Crohn’s disease (CD) and ulcerative colitis (UC)). However, little is known about the extent to which different diets reflect inflammation in IBD beyond measures such as faecal calprotectin or C-reactive protein. In this study, we aimed to unravel associations between dietary patterns and circulating inflammatory proteins in patients with IBD. Plasma concentrations of 73 different inflammation-related proteins were measured in 454 patients with IBD by proximity extension assay (PEA) technology. Food frequency questionnaires (FFQ) were used to assess habitual diet. Principal component analysis (PCA) was performed to extract data-driven dietary patterns. To identify associations between dietary patterns and plasma proteins, we used general linear models adjusting for age, sex, BMI, plasma storage time, smoking, surgical history and medication use. Stratified analyses were performed for IBD type, disease activity and protein intake. A high-sugar diet was strongly inversely associated with fibroblast growth factor-19 (FGF-19) independent of IBD type, disease activity, surgical history and deviance from recommended protein intake (false discovery rate (FDR) < 0.05). Conversely, a Mediterranean-style pattern was associated with higher FGF-19 levels (FDR < 0.05). A pattern characterised by high alcohol and coffee intake was positively associated with CCL11 (eotaxin-1) levels and with lower levels of IL-12B (FDR < 0.05). All results were replicated in CD, whereas only the association with FGF-19 was significant in UC. Our study suggests that dietary habits influence distinct circulating inflammatory proteins implicated in IBD and supports the pro- and anti-inflammatory role of diet. Longitudinal measurements of inflammatory markers, also postprandial, are needed to further elucidate the diet–inflammation relationship.

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“…Commensal microbiota in the gut also works in tandem with the host immune system to regulate homeostasis, by playing important roles in processes, such as nutrient metabolism and proper gastrointestinal development [ 69 ]. Though protective and beneficial in mucosal homeostasis and wound healing, excessive gut infiltration of immune cells, such as eosinophils and neutrophils, is associated with inflammatory conditions in the intestine [ 70 , 71 ]. Eosinophils and neutrophils are leukocytes that accumulate in the gut and are activated in times of infection and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Systematic Characterization of the Disruption of Intestine during Liver Tumor Progression in the xmrk Oncogene Transgenic Zebrafish Model

Lee

Lǚ

et al. 2022

Cells

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The crosstalk between tumors and their local microenvironment has been well studied, whereas the effect of tumors on distant tissues remains understudied. Studying how tumors affect other tissues is important for understanding the systemic effect of tumors and for improving the overall health of cancer patients. In this study, we focused on the changes in the intestine during liver tumor progression, using a previously established liver tumor model through inducible expression of the oncogene xmrk in zebrafish. Progressive disruption of intestinal structure was found in the tumor fish, displaying villus damage, thinning of bowel wall, increase in goblet cell number, decrease in goblet cell size and infiltration of eosinophils, most of which were observed phenotypes of an inflammatory intestine. Intestinal epithelial cell renewal was also disrupted, with decreased cell proliferation and increased cell death. Analysis of intestinal gene expression through RNA-seq suggested deregulation of genes related to intestinal function, epithelial barrier and homeostasis and activation of pathways in inflammation, epithelial mesenchymal transition, extracellular matrix organization, as well as hemostasis. Gene set enrichment analysis showed common gene signatures between the intestine of liver tumor fish and human inflammatory bowel disease, the association of which with cancer has been recently noticed. Overall, this study represented the first systematic characterization of the disruption of intestine under the liver tumor condition and suggested targeting intestinal inflammation as a potential approach for managing cancer cachexia.

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Role of Eosinophils in Intestinal Inflammation and Fibrosis in Inflammatory Bowel Disease: An Overlooked Villain?

Cited by 37 publications

References 220 publications

BordetellaSpp. Utilize T3SS To Promote Secretion of IL1RA Leading to Long-Term Persistent Infections

BordetellaSpp. Utilize T3SS To Promote Secretion of IL1RA Leading to Long-Term Persistent Infections

Long-Term Dietary Patterns Are Reflected in the Plasma Inflammatory Proteome of Patients with Inflammatory Bowel Disease

Systematic Characterization of the Disruption of Intestine during Liver Tumor Progression in the xmrk Oncogene Transgenic Zebrafish Model

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