The Immune Function of Tuft Cells at Gut Mucosal Surfaces and Beyond

Ting, Hung-An; Moltke, Jakob von

doi:10.4049/jimmunol.1801069

Cited by 88 publications

(83 citation statements)

References 105 publications

(209 reference statements)

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“…In the gut, it has been shown that tuft cell-derived IL-25 is required to mount a Th2 immune response to parasite infection. Tuft cell-derived IL-25 stimulates group 2 innate lymphoid cells (ILC2s) to produce IL-5, -9, and -13, promoting type 2 inflammation (Ting and von Moltke, 2019). IL-13 is sufficient to skew the lineage of undifferentiated intestinal epithelial cells toward tuft and mucin-producing goblet cells.…”

Section: Discussionmentioning

confidence: 99%

Tuft Cell Formation Reflects Epithelial Plasticity in Pancreatic Injury: Implications for Modeling Human Pancreatitis

et al. 2020

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Chronic pancreatitis, a known risk factor for the development of pancreatic ductal adenocarcinoma (PDA), is a serious, widespread medical condition characterized by inflammation, fibrosis, and acinar to ductal metaplasia (ADM). ADM is a cell type transdifferentiation event where pancreatic acinar cells become ductal-like under conditions of injury or oncogenic mutation. Here, we show that chronic pancreatitis and ADM in genetically wild type mice results in the formation of a significant population of chemosensory tuft cells. Transcriptomic analyses of pancreatitis tuft cells identify expression of inflammatory mediators, consistent with a role for tuft cells in injury progression and/or resolution. Though similar to tuft cell populations in other organs and disease systems, we identified a number of key differences that suggest contextspecific tuft cell functions. We evaluated seven different mouse strains for tuft cell formation in response to chronic injury and identified significant heterogeneity reflecting varying proclivity for epithelial plasticity between strains. These results have interesting implications in the role of epithelial plasticity and heterogeneity in pancreatitis and highlight the importance of mouse strain selection when modeling human disease.

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Section: Discussionmentioning

confidence: 99%

Tuft Cell Formation Reflects Epithelial Plasticity in Pancreatic Injury: Implications for Modeling Human Pancreatitis

et al. 2020

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“…6a). We next utilized gene set enrichment analysis (GSEA) to compare the transcriptome of drug treated BPN tumors to published/curated gene expression datasets for gastric epithelial cell types and tuft cells (Haber et al 2017;Leushacke et al 2017;Montoro et al 2018;Ting and von Moltke 2019;Zhang et al 2019). GSEA showed that signatures of both Lgr5-expressing gastric chief cells as well as tuft cells were significantly enriched in MAPK-inhibited BPN cells ( Fig.…”

Section: Mapk Pathway Regulates Identity Of Nkx2-1-negative Mucinousmentioning

confidence: 99%

An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma

Zewdu

Mehrabad

Ingram

et al. 2020

Preprint

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Cancer cells often undergo lineage switching during their natural progression and in response to therapy. Lung adenocarcinomas (LUADs) exhibit a variety of differentiation states accompanied by dysregulation of lineage-specific transcription factors such as NKX2-1. Loss of NKX2-1 in human and murine LUAD leads to invasive mucinous adenocarcinoma (IMA), a subtype of lung cancer that exhibits pulmonary to gastric transdifferentiation. Human IMAs harbor a distinct spectrum of mutationally activated driver oncogenes compared to LUAD overall, suggesting that the transdifferentiation induced by NKX2-1 loss plays a context-dependent role in LUAD progression. Using genetically engineered mouse models, we find that NKX2-1 is required for optimal BRAF V600E driven lung tumor initiation but is dispensable for growth of established lung tumors. NKX2-1-deficient, BRAF V600E driven tumors morphologically resemble human IMA, have high levels of ERK phosphorylation and exhibit a distinct response to treatment with combined BRAF/MEK inhibitors. Whereas NKX2-1-positive tumor cells enter quiescence when treated with BRAF/MEK inhibitors, residual NKX2-1-negative cells fail to exit the cell cycle in response to the same therapy. Additionally, BRAF/MEK inhibitors induce canonical WNT signaling in NKX2-1negative lung tumor cells, which is accompanied by cell identity switching within the gastric lineage. Co-inhibition of MAPK and WNT pathways blocked elements of this lineage switch in vitro and interfered with cell cycle changes imposed by MAPK inhibition in vivo. Our data show that there is a complex and reciprocal relationship between lineage specifiers and oncogenic signaling pathways in the regulation of LUAD identity and suggest that lineage switching induced by targeted therapies may confer new therapeutic vulnerabilities.

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“…Likewise, goblet cells secrete mucins and antimicrobials that are effective against bacteria and protozoa (Kim and Ho, 2010). On the other hand, tuft cells express IL-25 that is important in mounting a type 2 immune response to protect against certain helminths (Ting and von Moltke, 2019). Finally, different pathogens elicit different immune responses that result in an alteration of the intestinal epithelial cell composition that is important for effector responses (Biton et al, 2018;Lindholm et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Intestinal-epithelial LSD1 controls cytoskeletal-mediated cell identity including goblet cell effector responses required for gut inflammatory and infectious diseases

Parmar

Burrows

Lindholm

et al. 2020

Preprint

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ABSTRACTInfectious and inflammatory diseases in the intestine remain a serious threat for patients world-wide. Reprogramming of the intestinal epithelium towards a protective effector state is important to manage inflammation and immunity. The role of epigenetic regulatory enzymes within these processes is not yet defined. Here, we use a mouse model that has an intestinal-epithelial specific deletion of the histone demethylase Lsd1 (cKO mice), which maintains the epithelium in a fixed reparative state. Challenge of cKO mice with chemical-induced colitis, bacteria-induced colitis, and a helminth infection model all resulted in increased pathogenesis. Mechanistically, we discovered that LSD1 directly controls genes that facilitate cytoskeletal organization, and that this is relevant for epithelial attachment as well as for goblet-cell specific effector responses.This study therefore identifies intestinal-epithelial epigenetic regulation by LSD1 as a critical element in host protection from inflammation and infection.

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The Immune Function of Tuft Cells at Gut Mucosal Surfaces and Beyond

Cited by 88 publications

References 105 publications

Tuft Cell Formation Reflects Epithelial Plasticity in Pancreatic Injury: Implications for Modeling Human Pancreatitis

Tuft Cell Formation Reflects Epithelial Plasticity in Pancreatic Injury: Implications for Modeling Human Pancreatitis

An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma

Intestinal-epithelial LSD1 controls cytoskeletal-mediated cell identity including goblet cell effector responses required for gut inflammatory and infectious diseases

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