Tissue-infiltrating neutrophils represent the main source of IL-23 in the colon of patients with IBD

Kvedaraite, Egle; Lourda, Magda; Ideström, Maja; Chen, Puran; Olsson‐Åkefeldt, Selma; Forkel, Marianne; Gavhed, Désirée; Lindforss, Ulrik; Mjösberg, Jenny; Henter, Jan‐Inge; Svensson, Mattias

doi:10.1136/gutjnl-2014-309014

Cited by 95 publications

(69 citation statements)

References 56 publications

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“…For example, it was previously shown that, while Helicobacter pylori Neutrophil Activating Factor triggers the expression of IL‐23p19 mRNA by human neutrophils, Borrelia burgdorferi NapA, but not OspA, induces IL‐23 at both gene expression and protein level . In another study, both blood neutrophils and neutrophils infiltrating colon tissue of pediatric patients with inflammatory bowel disease were found to express IL‐23p19 (as revealed by immunohistochemistry and immunofluorescence), using an Ab detecting only the IL‐23p19 monomer, which is secreted by many cell types but is biologically inactive. More recently, human neutrophils (whose purity was not stated) were shown to express IL‐23 (presumably IL‐23p19) mRNA, as well as to produce very elevated levels of IL‐23 protein, when infected with Mycobacterium tuberculosis H37Rv or when incubated with either LPS or Pam3CSK4 (a TLR2 agonist) .…”

Section: Discussionmentioning

confidence: 97%

Human neutrophils activated via TLR8 promote Th17 polarization through IL-23

Tamassia

Arruda‐Silva

Wright

et al. 2019

Journal of Leukocyte Biology

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Human neutrophils contribute to the regulation of inflammation via the generation of a range of cytokines that affect all elements of the immune system. Here, we investigated their ability to express some of the members of the IL‐12 family after incubation with TLR8 agonists. Highly pure human neutrophils were thus incubated for up to 48 h with or without R848, or other TLR8 agonists, to then measure the expression levels of transcripts and proteins for IL‐12 family member subunits by RNA‐seq, reverse transcription quantitative PCR, and ELISA. We show a TLR8‐mediated inducible expression of IL‐12B and IL‐23A, but not IL‐12A, mRNA, which occurs via chromatin remodeling (as assessed by ChIP‐seq), and subsequent production of IL‐23 and IL‐12B, but no IL‐12, proteins. Induction of IL‐23 requires endogenous TNF‐α, as both mRNA and protein levels were blocked in TLR8‐activated neutrophils via a TNF‐α‐neutralizing Ab. We also show that supernatants from TLR8‐activated neutrophils, but not autologous monocytes, induce the differentiation of Th17 cells from naïve T cells in an IL‐23‐dependent fashion. This study unequivocally demonstrates that highly pure human neutrophils express and produce IL‐23, further supporting the key roles played by these cells in the important IL‐17/IL‐23 network and Th17 responses.

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Section: Discussionmentioning

confidence: 97%

Human neutrophils activated via TLR8 promote Th17 polarization through IL-23

Tamassia

Arruda‐Silva

Wright

et al. 2019

Journal of Leukocyte Biology

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“…A correlation between frequencies of neutrophils and endoscopic severity was reported in ulcerative colitis [4] and was proposed in Crohn's disease using quantification of fecal calprotectin or Indium-111 scanning [28,29]. However, apparently contradictory studies suggest that CD may result from a defect in neutrophil recruitment, and that recruited neutrophils are either dysfunctional or display proinflammatory functions [18,[30][31][32].…”

Section: Discussionmentioning

confidence: 99%

Recruitment of activated neutrophils correlates with disease severity in adult Crohn’s disease

Therrien

Chapuy

Bsat

et al. 2018

Clinical and Experimental Immunology

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Summary Neutrophils are detected in inflamed colon in Crohn’s disease (CD). However, whether the frequency and/or activation of circulating or gut tissue neutrophils correlate with endoscopic severity remains to be investigated. A cohort of 73 CD patients was prospectively enrolled according to endoscopic severity and treatment history. Individuals with active disease were stratified using the Montreal classification. Harvey–Bradshaw Index (HBI) and Simple Endoscopic Score for Crohn’s Disease (SES‐CD) were performed at the time of ileocolonoscopy. Frequency of neutrophils and their expression of CD66b and CD64 were assessed in paired blood and colonic biopsies using flow cytometry. The percentage of neutrophils increased in inflamed colon and correlated with SES‐CD in the entire cohort of patients examined, as well as in the subgroup with inflammatory (B1) active disease. SES‐CD further correlated with neutrophil CD66b expression in mucosa but not blood and, conversely, with neutrophil CD64 expression in blood but not mucosa. However, the evaluation of neutrophil activation in mucosa when compared to blood reflected disease activity more clearly. Finally, a neutrophil activation power index (CD66b in mucosa X CD64 in blood) that correlated with SES‐CD discriminated between patients with mild and severe disease. In conclusion, the frequency and activation of colonic neutrophils correlated with SES‐CD, highlighting that mucosal neutrophils are associated with disease severity in CD.

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“…Sources of IL23 include macrophages, dendritic cells, neutrophils, and epithelial cells 8,9,13,14 . Cells that produce IL17 (generally referring to IL17A, with 6 members in the family described) are also highly enriched in mucosal tissues 11 .…”

Section: Il23 and Th17 Cell Pathwaysmentioning

confidence: 99%

Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases

et al. 2017

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Insights into the pathogenesis of inflammatory bowel diseases (IBD) have provided important information for the development of therapeutics. Levels of interleukin 23 (IL23) and T-helper (Th) 17 cell pathway molecules are elevated in inflamed intestinal tissues of patients with IBD. Loss of function variants of the interleukin 23 receptor gene (IL23R) protect against IBD, and in animals, blocking IL23 reduces severity of colitis. These findings indicated that the IL23 and Th17 cell pathways might be promising targets for treatment of IBD. Clinical trials have investigated the effects of agents designed to target distinct levels of the IL23 and Th17 cell pathways, and the results are providing insights into IBD pathogenesis and additional strategies for modulating these pathways. Strategies to reduce levels of proinflammatory cytokines more broadly and increase anti-inflammatory mechanisms are also emerging for treatment of IBD. The results from trials targeting these immune system pathways have provided important lessons for future trials. Findings indicate the importance of improving approaches to integrate patient features and biomarkers of response with selection of therapeutics.

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Tissue-infiltrating neutrophils represent the main source of IL-23 in the colon of patients with IBD

Cited by 95 publications

References 56 publications

Human neutrophils activated via TLR8 promote Th17 polarization through IL-23

Human neutrophils activated via TLR8 promote Th17 polarization through IL-23

Recruitment of activated neutrophils correlates with disease severity in adult Crohn’s disease

Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases

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