Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression

Shaw, Tovah N.; Houston, Stephanie; Wemyss, Kelly; Bridgeman, Hayley; Barbera, Thomas; Zangerle-Murray, Tamsin; Patrick, Sheila; Ridley, Amanda J L; Wang, Ping; Tamoutounour, Samira; Allen, Judith E.; Konkel, Joanne E.; Grainger, John

doi:10.1084/jem.20180019

Cited by 301 publications

(366 citation statements)

References 60 publications

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“…Increased mRNA levels of Cd4 can be attributed to T cells, monocytes, macrophages or dendritic cells and, although it is not possible to determine the specific cell type associated with this increase, it may be reflective of an increase in tissue resident macrophages (Shaw et al . ). Increased duodenal mRNA levels of Tlr2 and Il6 are consistent with intestinal inflammation in HFD dams (Hausmann et al .…”

Section: Discussionmentioning

confidence: 97%

High‐fat diet intake modulates maternal intestinal adaptations to pregnancy and results in placental hypoxia, as well as altered fetal gut barrier proteins and immune markers

Gohir

Kennedy

Wallace

et al. 2019

The Journal of Physiology

109

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Key points Maternal obesity has been associated with shifts in intestinal microbiota, which may contribute to impaired barrier function Impaired barrier function may expose the placenta and fetus to pro‐inflammatory mediators We investigated the impacts of diet‐induced obesity in mice on maternal and fetal intestinal structure and placental vascularization Diet‐induced obesity decreased maternal intestinal short chain fatty acids and their receptors, impaired gut barrier integrity and was associated with fetal intestinal inflammation. Placenta from obese mothers showed blood vessel immaturity, hypoxia, increased transcript levels of inflammation, autophagy and altered levels of endoplasmic reticulum stress markers. These data suggest that maternal intestinal changes probably contribute to adverse placental adaptations and also impart an increased risk of obesity in the offspring via alterations in fetal gut development. Abstract Shifts in maternal intestinal microbiota have been implicated in metabolic adaptations to pregnancy. In the present study, we generated cohorts of female C57BL/6J mice fed a control (17% kcal fat, n = 10–14) or a high‐fat diet (HFD 60% kcal from fat, n = 10–14; ad libitum) aiming to investigate the impact on the maternal gut microbiota, intestinal inflammation and gut barrier integrity, placental inflammation and fetal intestinal development at embryonic day 18.5. HFD was associated with decreased relative abundances of short‐chain fatty acid (SCFA) producing genera during pregnancy. These diet‐induced shifts paralleled decreased maternal intestinal mRNA levels of SCFA receptor Gpr41, modestly decreased cecal butyrate, and altered mRNA levels of inflammatory cytokines and immune cell markers in the maternal intestine. Maternal HFD resulted in impaired gut barrier integrity, with corresponding increases in circulating maternal levels of lipopolysaccharide (LPS) and tumour necrosis factor. Placentas from HFD dams demonstrated blood vessel immaturity and hypoxia; decreased free carnitine, acylcarnitine derivatives and trimethylamine‐N‐oxide; and altered mRNA levels of inflammation, autophagy, and ER stress markers. HFD exposed fetuses had increased activation of nuclear factor‐kappa B and inhibition of the unfolded protein response in the developing intestine. Taken together, these data suggest that HFD intake prior to and during pregnancy shifts the composition of the maternal gut microbiota and impairs gut barrier integrity, resulting in increased maternal circulating LPS, which may ultimate contribute to changes in placental vascularization and fetal gut development.

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Section: Discussionmentioning

confidence: 97%

High‐fat diet intake modulates maternal intestinal adaptations to pregnancy and results in placental hypoxia, as well as altered fetal gut barrier proteins and immune markers

Gohir

Kennedy

Wallace

et al. 2019

The Journal of Physiology

109

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“…Notably, the majority of the cells we retrieve likely comprise lamina propria / mucosa resident macrophages, rather than the less abundant macrophages of the submucosa or muscularis layer 10,11 . Generation of a CD4 + Timd4 + subpopulation of lamina propria macrophages was reported to require prolonged residence in the tissue 10 . Although grafted cells in both colon and ileum acquired with time some expression of a hallmark of the long-lived cells, the phosphatidyl serine receptor Timd4 (Tim4) ( Fig.…”

Section: Transcriptomes Of Engrafted Cells Differ From Resident Macromentioning

confidence: 97%

“…These differences might be attributable to incomplete macrophage maturation or to the recently reported heterogeneity of the intestinal macrophage compartment 10,11 . Notably, the majority of the cells we retrieve likely comprise lamina propria / mucosa resident macrophages, rather than the less abundant macrophages of the submucosa or muscularis layer 10,11 . Generation of a CD4 + Timd4 + subpopulation of lamina propria macrophages was reported to require prolonged residence in the tissue 10 .…”

Section: Transcriptomes Of Engrafted Cells Differ From Resident Macromentioning

confidence: 98%

“…Recent studies revealed that monocyte-derived lamina propria macrophages comprise in mice two populations, i.e. short-lived cells and long-lived cells with self-renewing capacity 10 ; the latter population might also include remnants of embryonic populations, as could additional intestinal long-lived macrophage populations that reside near blood vessels, nerves and in the Peyer's patches 11 . Evidence for macrophages with different half-lives is also emerging for the human small intestine 12 .…”

Section: Introductionmentioning

confidence: 99%

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Defining Monocyte Differentiation into Colonic and Ileal Macrophages

Gross-Vered

Shemer

Bernshtein

et al. 2019

Preprint

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Monocytes are circulating short-lived macrophage precursors that are recruited on demand from the blood to sites of inflammation and challenge. In steady state, classical monocytes give rise to vasculature-resident cells that patrol the luminal side of the endothelium. In addition, classical monocytes feed macrophage compartments of selected organs, including barrier tissues, such as the skin and intestine, as well as the heart. Monocyte differentiation under conditions of inflammation has been studied in considerable detail. In contrast, monocyte differentiation under non-inflammatory conditions remains less well understood.Here we took advantage of a combination of cell ablation and precursor engraftment to investigate the generation of gut macrophages from monocytes. Collectively, we identify factors associated with the gradual adaptation of monocytes to tissue residency. Moreover, comparison of monocyte differentiation into the colon and ileum-resident macrophages revealed the graduated acquisition of gut segment-specific gene expression signatures.

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“…The majority of macrophages in the intestine are seeded by Ly6C hi blood monocytes in a largely CCR2‐dependent manner . However, recent evidence in mice indicates that a separate population of CCR2‐independent intestinal macrophages exists in the gut; these are long‐lived cells that express the markers Tim4 and CD4 . These macrophages are present perinatally and play an essential role in intestinal physiology .…”

Section: Intestinementioning

confidence: 99%

Regulation of mononuclear phagocyte function by the microbiota at mucosal sites

Scott

Mann

2019

Immunology

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Summary Mucosal tissues contain distinct microbial communities that differ drastically depending on the barrier site, and as such, mucosal immune responses have evolved to be tailored specifically for their location. Whether protective or regulatory immune responses against invading pathogens or the commensal microbiota occur is controlled by local mononuclear phagocytes (MNPs). Comprising macrophages and dendritic cells (DCs), the functions of these cells are highly dependent on the local environment. For example, the intestine contains the greatest bacterial load of any site in the body, and hence, intestinal MNPs are hyporesponsive to bacterial stimulation. This is thought to be one of the major mechanisms by which harmful immune responses directed against the trillions of harmless bacteria that line the gut lumen are avoided. Regulation of MNP function by the microbiota has been characterized in the most depth in the intestine but there are several mucosal sites that also contain their own microbiota. In this review, we present an overview of how MNP function is regulated by the microbiota at mucosal sites, highlighting recent novel pathways by which this occurs in the intestine, and new studies elucidating these interactions at mucosal sites that have been characterized in less depth, including the urogenital tract.

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Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression

Cited by 301 publications

References 60 publications

High‐fat diet intake modulates maternal intestinal adaptations to pregnancy and results in placental hypoxia, as well as altered fetal gut barrier proteins and immune markers

High‐fat diet intake modulates maternal intestinal adaptations to pregnancy and results in placental hypoxia, as well as altered fetal gut barrier proteins and immune markers

Defining Monocyte Differentiation into Colonic and Ileal Macrophages

Regulation of mononuclear phagocyte function by the microbiota at mucosal sites

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