CD16+ Macrophages Mediate Fibrosis in Inflammatory Bowel Disease

Salvador, P.; Macias-Ceja, D C; Gisbert-Ferrándiz, Laura; Hernández, Carlos; Bernardo, David; Alós, Rafael; Navarro-Vicente, F; Esplugues, Juan V.; Ortiz-Masiá, Dolores; Barrachina, Dolores; Calatayud, Sara

doi:10.1093/ecco-jcc/jjx185

Cited by 32 publications

(28 citation statements)

References 32 publications

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“…It seems likely that these differences, rather than cause, are consequence of the different extent of fibrosis, which in turn depends on the presence of sucnr1 in those cells of the transplanted tissue mediating the fibrotic response. Of interest, graphs from both groups showed an increased expression of CD16, a recently reported marker of pro-fibrotic macrophages, 28 and of the well-known fibrogenic mediator, TGFβ. 1 The presence of similar levels of these pro-fibrotic elements in both, WT and Sucnr1 −/− mice suggest that fibrosis, in the heterotopic transplant model, may depend mainly on the pro-inflammatory cytokines, although, a reduced cellular reactivity to fibrogenesis resulting from the lack of Sucnr1 in intestinal tissue cannot be ruled out.…”

Section: Discussionmentioning

confidence: 85%

Succinate receptor mediates intestinal inflammation and fibrosis

et al. 2019

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Succinate, an intermediate of the tricarboxylic acid cycle, is accumulated in inflamed areas and its signaling through succinate receptor (SUCNR1) regulates immune function. We analyze SUCNR1 expression in the intestine of Crohn's disease patients and its role in murine intestinal inflammation and fibrosis. We show that both serum and intestinal succinate levels and SUCNR1 expression in intestinal surgical resections were higher in CD patients than in controls. SUCNR1 co-localized with CD86, CD206, and α-SMA+ cells in human intestine and we found a positive and significant correlation between SUCNR1 and α-SMA expression. In human isolated fibroblasts from CD patients SUCNR1 expression was higher than in those from controls and treatment with succinate increased SUCNR1 expression, fibrotic markers and inflammatory cytokines through SUCNR1. This receptor modulated the expression of pro-inflammatory cytokines in resting murine macrophages, macrophage polarization and fibroblast activation and Sucnr1 −/− mice were protected against both acute TNBS-colitis and intestinal fibrosis induced by the heterotopic transplant of colonic tissue. We demonstrate increased succinate levels in serum and SUCNR1 expression in intestinal tissue of CD patients and show a role for SUCNR1 in murine intestinal inflammation and fibrosis.

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Section: Discussionmentioning

confidence: 85%

Succinate receptor mediates intestinal inflammation and fibrosis

et al. 2019

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“…More precisely, the number of intestinal IL-36α + Mfs increase in the colon of Crohn's patients with stenosis (298). Functionally, IL-36 acted directly on human mesenchymal cells to elicit a profibrotic transcriptional program (298), suggesting that the increase of IL-36α + Mfs could induce intestinal fibrosis during chronic inflammation in IBD patients (298)(299)(300). Corroborating this, Martin et al recently showed in situ that immature Mfs were always in the close vicinity of activated fibroblasts in intestinal mucosa of Crohn's patients (263).…”

Section: Function Of Intestinal Mucosa Macrophagesmentioning

confidence: 99%

Human Intestinal Mononuclear Phagocytes in Health and Inflammatory Bowel Disease

Caër

Wick

2020

Front. Immunol.

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Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a complex immune-mediated disease of the gastrointestinal tract that increases morbidity and negatively influences the quality of life. Intestinal mononuclear phagocytes (MNPs) have a crucial role in maintaining epithelial barrier integrity while controlling pathogen invasion by activating an appropriate immune response. However, in genetically predisposed individuals, uncontrolled immune activation to intestinal flora is thought to underlie the chronic mucosal inflammation that can ultimately result in IBD. Thus, MNPs are involved in fine-tuning mucosal immune system responsiveness and have a critical role in maintaining homeostasis or, potentially, the emergence of IBD. MNPs include monocytes, macrophages and dendritic cells, which are functionally diverse but highly complementary. Despite their crucial role in maintaining intestinal homeostasis, specific functions of human MNP subsets are poorly understood, especially during diseases such as IBD. Here we review the current understanding of MNP ontogeny, as well as the recently identified human intestinal MNP subsets, and discuss their role in health and IBD.

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“…For instance, the compartment of myeloid mononuclear cells including dendritic cells [DCs] and macrophages has not been characterised in detail. Effects of macrophages on intestinal fibrosis have been demonstrated, 65,66 and our results do not exclude a modulation of frequency, activation level, and/ or phenotype of macrophages or DCs, which remains a limitation of our study.…”

Section: Discussionmentioning

confidence: 55%

The Oxysterol Synthesising Enzyme CH25H Contributes to the Development of Intestinal Fibrosis

Raselli

Wyss

Alvarado

et al. 2019

Journal of Crohn's and Colitis

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Intestinal fibrosis and stenosis are common complications of Crohn’s disease [CD], frequently requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, anti-fibrotic therapies remain an unmet clinical need. Oxysterols are oxidised cholesterol derivatives with important roles in various biological processes. The enzyme cholesterol 25-hydroxylase [CH25H] converts cholesterol to 25-hydroxycholesterol [25-HC], which modulates immune responses and oxidative stress. In human intestinal samples from CD patients, we found a strong correlation of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced intestinal fibrosis in mice deficient for the CH25H enzyme, using the sodium dextran sulphate [DSS]-induced chronic colitis model. Additionally, using a heterotopic transplantation model of intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the pathogenesis of intestinal fibrosis.

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CD16+ Macrophages Mediate Fibrosis in Inflammatory Bowel Disease

Abstract: Our study demonstrates that STAT6 deficiency dysregulates the macrophage response to inflammatory outbursts by increasing the presence of a population of CD16+ macrophages that seems to contribute to intestinal fibrosis.

Cited by 32 publications

References 32 publications

Succinate receptor mediates intestinal inflammation and fibrosis

Succinate receptor mediates intestinal inflammation and fibrosis

Human Intestinal Mononuclear Phagocytes in Health and Inflammatory Bowel Disease

The Oxysterol Synthesising Enzyme CH25H Contributes to the Development of Intestinal Fibrosis

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