An Independent Subset of TLR Expressing CCR2-Dependent Macrophages Promotes Colonic Inflammation

Platt, Andrew M.; Bain, Calum C.; Bordon, Yvonne; Sester, David P.; Mowat, Allan McI

doi:10.4049/jimmunol.0903987

Cited by 179 publications

(195 citation statements)

References 42 publications

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“…This finding was in line with previous studies showing the association of Ly-6C hi -derived DCs with progression of intestinal inflammation (20). Next, we tested DCs isolated from Ccr2 −/− mice that have reduced levels of circulating Ly-6C hi cells (21). CD11c + DC subpopulations isolated from MLNs showed a twofold decrease in Ly-6C hi cells and (Fig.…”

Section: Significancesupporting

confidence: 77%

“…We show that MLN-derived CD11c + DCs sense 3SL and mediate proinflammatory properties such as increased secretion of inflammatory cytokines (e.g., IL-6, IL-12, and TNF-α). Ccr2 −/− mice have generally reduced levels of Ly6C hi cells and are also less susceptible to DSS-induced colitis (21). We detected low levels of CD11c + /Ly6C + cells in MLNs of Ccr2 −/− mice and these cells were also less responsive to stimulation with 3SL.…”

Section: Discussionmentioning

confidence: 69%

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Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c ⁺ cells through TLR4

Kurakevich

Hennet

Hausmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Breast milk oligosaccharides shape the intestinal environment by affecting mucosal immunity and bacterial colonization. To clarify the role of milk oligosaccharide sialyl(α2,3)lactose (3SL) in intestinal physiology and disease, we investigated colitis development in Il10 −/− mice exposed to normal or 3SL-deficient milk during lactation. Onset and progression of intestinal inflammation were delayed in Il10 −/− mice deficient for the α2,3 sialyltransferase 4 (ST3GAL4) responsible for 3SL biosynthesis. The proinflammatory role of 3SL was confirmed by showing that oral supplementation of newborn Il10 −/− ;St3gal4 −/− mice with 3SL increased colitis severity. Conversely, fostering of newborn Il10 −/− mice to lactating St3gal4 −/− mothers reduced colitis severity. 3SL directly stimulated mesenteric lymph node CD11c + dendritic cells and induced production of cytokines required for expansion of T H 1 and T H 17 T cells. The stimulatory effect of 3SL was attenuated in Tlr4-deficient CD11c + cells, demonstrating that 3SL induces inflammation through Toll-like receptor 4 (TLR4) signaling. Thus, 3SL directly modulates mucosal immunity, which increases susceptibility to colitis.carbohydrate | glycan | prebiotics | mouse innate immunity I nflammatory bowel disease (IBD) affects up to 0.8% of the Western population and this number is constantly growing worldwide (1). The etiology of IBD is not fully understood, although a number of genetic and environmental factors leading to aberrant mucosal immune responses have been identified (2). Nutrition and especially breastfeeding affects the risk for IBD (3). Breastfeeding for at least 3 mo, accordingly, contributes to a lower incidence for IBD (4); however, these data still are controversial. Oligosaccharides are major constituents of breast milk fulfilling various functions, such as promoting growth of beneficial bacteria, acting as soluble receptors preventing attachment of pathogens in the gastrointestinal tract, and reducing adhesion of leukocytes (4, 5). The exact functions of individual oligosaccharides remain however largely unknown.The limited structural diversity of mouse milk oligosaccharides, including only sialyl(α2,3)lactose (3SL) and sialyl(α2,6)lactose (6SL), enables assessing the specific functional contribution of these oligosaccharides to intestinal homeostasis (6). A recent study provided unique evidence that milk-derived 3SL, but not 6SL, increased susceptibility to dextran sulfate sodium (DSS)-induced acute colitis (6). These findings indicate that individual milk oligosaccharides may not only mediate protective effects, but may promote inflammation as well.Mucosal innate immunity has a pivotal role in regulating inflammatory responses (2). Dendritic cells (DCs) and macrophages sense luminal antigens and provide signals for induction of tolerance to ingested antigens and commensal bacteria or for initiation of inflammatory immune responses, facilitating activation of adaptive immunity (7,8). Intestinal DCs consist of two functionally distinct subsets based on e...

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Section: Significancesupporting

confidence: 77%

Section: Discussionmentioning

confidence: 69%

Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c ⁺ cells through TLR4

Kurakevich

Hennet

Hausmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Intestinal Mjs are the most abundant MP in the gut, especially in the large intestine, where they comprise approximately one-fifth of all leucocytes and greatly outnumber DCs [4,5]. Most of these Mjs are in the LP below the epithelial monolayer, although some can also extend transepithelial dendrites into the intestinal lumen, a phenomenon that spurred much of the recent interest in intestinal MPs when it was thought to be due to DCs (Fig.…”

Section: Macrophages and Intestinal Immunitymentioning

confidence: 99%

“…During inflammation and/or infection the composition of the intestinal Mj pool changes dramatically, with infiltration by TLR-responsive Mjs that produce high levels of pro-inflammatory cytokines and chemokines [5,15]. An important question is how these inflammatory Mjs are related to the normally unresponsive, resident cells.…”

Section: Intestinal Macrophages In Inflammationmentioning

confidence: 99%

Intestinal macrophages – specialised adaptation to a unique environment

Bain

Mowat

2011

Eur J Immunol

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Interest in intestinal mononuclear phagocytes (MPs), both DCs and macrophages (Mφs), has exploded in the recent years. In this Viewpoint we will detail how resident intestinal lamina propria (LP) Mφs possess distinctive properties that reflect adaptation to a unique microenvironment. They play quite different roles in the normal and inflamed mucosa and, as we will show, the existing paradigms of differentiated Mφ subsets and of ‘resident’ versus ‘inflammatory’ monocytes based on other tissues may not apply to the gut. Strategies for targeting Mφs as a means of dampening intestinal inflammation will need to take account of these unique characteristics.

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“…CX 3 CR1 hi M s contribute to the intestinal LP homeostasis through the production of anti-inflammatory cytokines and the clearance of commensal bacteria that breach the epithelial barrier [4]. In contrast, during intestinal inflammation, microenvironmental signals promote the differentiation of extravasated monocytes into proinflammatory M s with the ability to produce interleukin (IL)-12, IL-23, tumor necrosis (TNF)-α and inducible nitric oxide synthase (iNOS) [5][6][7]. However, little is known about the developmental trajectories that lead extravasated monocytes to either antior proinflammatory intestinal M s. This is primarily due to the fact that a surface marker permitting unequivocal identification of M s within the intestine and their distinction from dendritic cells (DCs) is lacking.…”

mentioning

confidence: 99%

CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1‐inducing role of mesenteric lymph node macrophages during colitis

et al. 2012

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Dendritic cells (DCs) and monocyte-derived macrophages (M s) are key components of intestinal immunity. However, the lack of surface markers differentiating M s from DCs has hampered understanding of their respective functions. Here, we demonstrate that, using CD64 expression, M s can be distinguished from DCs in the intestine of both mice and humans. On that basis, we revisit the phenotype of intestinal DCs in the absence of contaminating M s and we delineate a developmental pathway in the healthy intestine that leads from newly extravasated Ly-6C hi monocytes to intestinal M s. We determine how inflammation impacts this pathway and show that T cell-mediated colitis is associated with massive recruitment of monocytes to the intestine and the mesenteric lymph node (MLN). There, these monocytes differentiate into inflammatory M s endowed with phagocytic activity and the ability to produce inducible nitric oxide synthase. Eur. J. Immunol. 2012. 42: 3150-3166 HIGHLIGHTS 3151 IntroductionThe intestinal lamina propria (LP) contains cells that express high levels of CX 3 CR1, the receptor for the fractalkine chemokine [1,2]. Based on their monocytic origin and on their inability to migrate to the mesenteric lymph nodes (MLNs) such CX 3 CR1 hi cells have been defined as macrophages (M s) [1][2][3]. CX 3 CR1 hi M s contribute to the intestinal LP homeostasis through the production of anti-inflammatory cytokines and the clearance of commensal bacteria that breach the epithelial barrier [4]. In contrast, during intestinal inflammation, microenvironmental signals promote the differentiation of extravasated monocytes into proinflammatory M s with the ability to produce interleukin (IL)-12, IL-23, tumor necrosis (TNF)-α and inducible nitric oxide synthase (iNOS) [5][6][7]. However, little is known about the developmental trajectories that lead extravasated monocytes to either antior proinflammatory intestinal M s. This is primarily due to the fact that a surface marker permitting unequivocal identification of M s within the intestine and their distinction from dendritic cells (DCs) is lacking. The interstitial DCs (Int-DCs) present throughout the LP derive from blood precursors known as pre-DCs [2]. Under steady-state conditions, the Int-DCs found in the intestinal LP induce oral tolerance by carrying antigens originating from food or from harmless bacteria to the MLNs [8,9]. The CD103 + Int-DCs found in the steady-state LP have the selective ability to express aldehyde dehydrogenase (ALDH) and thereby produce retinoic acid (RA). As a result, upon migration to MLNs they trigger the differentiation of naive CD4 + T cells specific for food and microbiota antigens into induced Foxp3 + regulatory T (iTreg) cells [10][11][12][13]. In contrast, the Int-DCs that develop in inflamed LP upon exposure to pathogens lose their capacity to generate iTreg cells and, upon migration to the MLNs, trigger the differentiation of naive, antigen-responsive CD4 + T cells into T helper type 1 (Th1) cells that are specific for the invading patho...

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An Independent Subset of TLR Expressing CCR2-Dependent Macrophages Promotes Colonic Inflammation

Abstract: Material

Cited by 179 publications

References 42 publications

Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c ⁺ cells through TLR4

Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c ⁺ cells through TLR4

Intestinal macrophages – specialised adaptation to a unique environment

CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1‐inducing role of mesenteric lymph node macrophages during colitis

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An Independent Subset of TLR Expressing CCR2-Dependent Macrophages Promotes Colonic Inflammation

Abstract: Material

Cited by 179 publications

References 42 publications

Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c + cells through TLR4

Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c + cells through TLR4

Intestinal macrophages – specialised adaptation to a unique environment

CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1‐inducing role of mesenteric lymph node macrophages during colitis

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Product

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Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c ⁺ cells through TLR4

Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c ⁺ cells through TLR4