Crucial role of plasmacytoid dendritic cells in the development of acute colitis through the regulation of intestinal inflammation

Arimura, Keiichi; Takagi, Hideaki; Uto, Takuhiro; Fukaya, Takao; Nakamura, Takeshi; Choijookhuu, Narantsog; Hishikawa, Yoshitaka; Yamashita, Yuichi; Sato, Katsuaki

doi:10.1038/mi.2016.96

Cited by 41 publications

(51 citation statements)

References 47 publications

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“…In contrast to our observations, pDCs were previously proposed to play an important role in colitis, exacerbating the overall IBD pathogenesis ( 29 , 30 ). Using Siglec-H DTR knock in mice to inducibly deplete pDCs following DT treatment, Arimura et al .…”

Section: Discussioncontrasting

confidence: 99%

“…While IFN-I clearly plays an important role in the development of colitis in Was -deficient animals, whether such IFN-I originates from pDCs and whether pDCs contribute at all to the overall pathology in this model was not tested. Finally, a recent study used genetic ablation of pDCs in an experimental model of colitis induced by dextran sodium sulfate (DSS) treatment and concluded that pDCs play a pathogenic role in IBD ( 30 ). However, in this model pDC ablation was achieved by diphtheria toxin (DT) treatment of Siglec H-DTR mice, which also depletes subsets of macrophages and DC progenitors, calling into question its specificity ( 31 ).…”

Section: Introductionmentioning

confidence: 99%

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Plasmacytoid Dendritic Cells Are Largely Dispensable for the Pathogenesis of Experimental Inflammatory Bowel Disease

et al. 2018

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Inflammatory bowel disease (IBD) is a chronic inflammatory condition caused by an aberrant immune response to microbial components of the gastrointestinal tract. Plasmacytoid dendritic cells (pDCs) are innate immune cells specialized in the production of type I interferons and were recently implicated in the pathogenesis of autoimmune disorders such as lupus and scleroderma. While pDCs were shown to infiltrate intestinal mucosa of IBD patients and proposed to participate in intestinal inflammation, their net contribution to the disease remains unclear. We addressed this question by targeting the pDC-specific transcription factor TCF4 (E2-2) in experimental IBD caused by deficiency of Wiskott-Aldrich syndrome protein (WASP) or of interleukin-10 (IL-10). Monoallelic Tcf4 deletion, which was previously shown to abrogate experimental lupus, did not affect autoimmunity manifestations or colitis in WASP-deficient animals. Furthermore, conditional biallelic Tcf4 targeting resulted in a near-complete pDC ablation, yet had no effect on the development of colitis in IL-10-deficient mice. Our results suggest that, in contrast to other inflammatory and autoimmune diseases, pDCs do not play a major role in the pathogenesis of intestinal inflammation during IBD.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Plasmacytoid Dendritic Cells Are Largely Dispensable for the Pathogenesis of Experimental Inflammatory Bowel Disease

et al. 2018

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“…pDCs are type-I IFN-producing cells that bridge the innate and adaptive immune systems [32] and are specialised in endosomal TLR7/9-mediated recognition of viral nucleic acids with their response involving massive secretion of type-I IFNs to promote virus removal [39]. .…”

Section: Discussionmentioning

confidence: 99%

Correlation Between Immune Lymphoid Cells and Plasmacytoid Dendritic Cells in Human Colon Cancer

Wu¹,

Cheng²,

Li³

et al. 2020

Preprint

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Background: Innate lymphoid cells (ILCs), so far studied mostly in mouse models, are important tissue-resident innate immune cells that play important roles in the colorectal cancer microenvironment and maintain the mucosal tissue homeostasis. Plasmacytoid dendritic cells (pDCs) present complexity in various tumour types and are correlated with poor prognosis. pDCs can promote HIV-1–induced group 3 ILC (ILC3) depletion through the CD95 pathway. However, the role of ILC3s in human colon cancer and their correlation with other immune cells, especially pDCs, remain unclear. Methods: We characterised ILCs and pDCs in the tumour microenvironment of 58 colon cancer patients by flow cytometry and selected three patients for RNA sequencing. Results: ILC3s were negatively correlated, and pDCs were positively correlated, with cancer pathological grade. There was a negative correlation between the numbers of ILC3s and pDCs in tumour tissues. RNA sequencing confirmed the correlations between ILC3s and pDCs and highlighted the potential function of many ILC- and pDC-associated differentially expressed genes in the regulation of tumour immunity. pDCs can induce apoptosis of ILC3s through the CD95 pathway in the tumour microenvironment. Conclusions: One of the interactions between ILC3s and pDCs is via the CD95 pathway, which may help explain the role of ILC3s in colon cancer.

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“…Both cDCs and pDCs can exacerbate acute DSS-induced colitis (11)(12)(13), and we compared the effects of adoptive transfer of wild-type DCs versus Lrba −/− DCs on DSS-induced colitis in wild-type recipient mice. BM cells were differentiated in vitro to yield BMDCs and BMpDCs, which were transferred to wild-type mice on day 0 and day 3 of the DSS challenge.…”

Section: Susceptibility To Dss-induced Colitis Caused By Nonsense Mutmentioning

confidence: 99%

Enhanced susceptibility to chemically induced colitis caused by excessive endosomal TLR signaling in LRBA-deficient mice

Wang

Zhan

McAlpine

et al. 2019

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

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LPS-responsive beige-like anchor (LRBA) protein deficiency in humans causes immune dysregulation resulting in autoimmunity, inflammatory bowel disease (IBD), hypogammaglobulinemia, regulatory T (Treg) cell defects, and B cell functional defects, but the cellular and molecular mechanisms responsible are incompletely understood. In an ongoing forward genetic screen for N-ethyl-N-nitrosourea (ENU)-induced mutations that increase susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice, we identified two nonsense mutations in Lrba. Although Treg cells have been a main focus in LRBA research to date, we found that dendritic cells (DCs) contribute significantly to DSS-induced intestinal inflammation in LRBA-deficient mice. Lrba−/− DCs exhibited excessive IRF3/7- and PI3K/mTORC1-dependent signaling and type I IFN production in response to the stimulation of the Toll-like receptors (TLRs) 3, TLR7, and TLR9. Substantial reductions in cytokine expression and sensitivity to DSS in LRBA-deficient mice were caused by knockout of Unc93b1, a chaperone necessary for trafficking of TLR3, TLR7, and TLR9 to endosomes. Our data support a function for LRBA in limiting endosomal TLR signaling and consequent intestinal inflammation.

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Crucial role of plasmacytoid dendritic cells in the development of acute colitis through the regulation of intestinal inflammation

Cited by 41 publications

References 47 publications

Plasmacytoid Dendritic Cells Are Largely Dispensable for the Pathogenesis of Experimental Inflammatory Bowel Disease

Plasmacytoid Dendritic Cells Are Largely Dispensable for the Pathogenesis of Experimental Inflammatory Bowel Disease

Correlation Between Immune Lymphoid Cells and Plasmacytoid Dendritic Cells in Human Colon Cancer

Enhanced susceptibility to chemically induced colitis caused by excessive endosomal TLR signaling in LRBA-deficient mice

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