Selective expression of constitutively activated STAT6 in intestinal epithelial cells promotes differentiation of secretory cells and protection against helminths

Schubart, Christoph; Krljanac, Branislav; Otte, Manuel; Symowski, Cornelia; Martini, Eva; Günther, Claudia; Becker, Christoph; Daniel, Christoph; Voehringer, David

doi:10.1038/s41385-018-0107-3

Cited by 22 publications

(31 citation statements)

References 39 publications

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“…This is consistent with reduced IL-22 signaling (75) and altered goblet cell development (79)). In addition, STAT6, a key regulator of secretory lineage differentiation, was predicted to have lower activity in OLFM4 expressing stem cells and immature enterocytes (80). This is consistent with predicted upregulation of MYC in secretory precursors and goblet cells, which negatively regulates differentiation towards goblet cells (81).…”

Section: Us Cohortssupporting

confidence: 71%

Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation in severe disease

Kummerlowe

Wallach

Mwakamui

et al. 2021

Preprint

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Environmental enteropathy (EE) is a subclinical condition of the small intestine that is highly prevalent in low- and middle income countries. It is thought to be a primary cause of most global growth-stunting cases and a key contributing factor to childhood malnutrition and diminished oral vaccine responses. While EE has been shown to be the byproduct of recurrent enteric infection, to date, its full pathophysiology remains unclear. Here, we mapped the cellular and molecular correlates of EE severity by performing high-throughput single-cell RNA-sequencing on 33 small intestinal biopsies from 11 adults with EE from Lusaka, Zambia (8 HIV negative, 3 HIV positive) and 6 adults without EE in Boston, USA. Using the resulting cellular atlas, we scored existing bulk-transcriptomic signatures of reduced villus height and decreased plasma LPS levels in EE, finding that these signatures may be driven by an increased abundance of surface mucosal cells (a gastric-like subset previously implicated in epithelial repair in the gastrointestinal tract). In addition, we identified several cell subsets whose fractional abundances associated with histological determined EE severity, small intestinal region, and HIV infection. Furthermore, by comparing distal duodenal EE samples with those from two U.S. control cohorts, we identified broadly decreased epithelial proliferative signaling, lower fractional abundances of goblet cells, and a T cell subset highly expressing a transcriptional signature of tissue-resident memory cells but with increased pro-inflammatory cytokine expression in EE. Altogether, our work illuminates the epithelial and immune correlates of EE severity and provides new molecular targets for intervention.

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Section: Us Cohortssupporting

confidence: 71%

Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation in severe disease

Kummerlowe

Wallach

Mwakamui

et al. 2021

Preprint

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“…Gastrointestinal helminth infection represents one of the most widespread chronic human parasitoses and several mouse models serve as well‐established tools to study helminth‐induced type 2 immune responses and cytokine regulation . Mice infected with the rodent nematode Nippostrongylus brasiliensis ( Nb ) have revealed that the protective anti‐helminth immunity is largely dependent on IL‐4/IL‐13‐induced STAT6 activation . Using T cell‐specific IL‐4/IL‐13‐deficient mice (4‐13Tko), we previously showed that IL‐4/IL‐13 produced by cells of the innate immune system is required for effective type 2 immune responses against Nb .…”

Section: Introductionmentioning

confidence: 99%

Th2 cell‐derived IL‐4/IL‐13 promote ILC2 accumulation in the lung by ILC2‐intrinsic STAT6 signaling in mice

Symowski

Voehringer

2019

Eur J Immunol

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Type 2 innate lymphoid cells (ILC2s) are largely tissue-resident cytokine-secreting effector cells associated with allergic inflammation and protective immunity against helminths. Mechanisms that regulate the population dynamics of ILC2s in tissues are poorly understood. In this issue, Symowski C. and Voehringer D. show that Th2 cell-derived IL-4/IL-13 enhance the proliferation and accumulation of ILC2s in the lung of mice infected with the helminth Nippostrongylus brasiliensis. By generating mixed bone marrow chimeras, the authors could demonstrate that this effect requires ILC2-intrinsic expression of STAT6. STAT6-deficient ILC2s showed lower expression of MHC class II molecules on the cell surface suggesting that ILC2s may communicate directly with Th2 cells and receive an antigen-dependent positive feedback signal that leads to ILC2 accumulation in the lung.

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“…We do not know the specific time for the pathological transformation of the IL-4/STAT6 signaling pathway favoring CAC development such that it is detrimental to the immune response. In fact, during steady-state conditions, IL4R downstream transcription factor STAT6 promotes the proliferation and differentiation of secretory intestinal epithelial cells (IECs) in normal colon tissue [ 56 ]. Not only that, STAT6 overactivation in IECs has been associated with loss of the tight junctions that leads to permeability dysregulation, bacterial translocation and changes in the microbiome, as well as intestinal inflammation and tumorigenesis [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Recruitment of M1 Macrophages May Not Be Critical for Protection against Colitis-Associated Tumorigenesis

Medina-Andrade

Guerrero-García

Espinosa

et al. 2021

IJMS

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A close connection between inflammation and the risk of developing colon cancer has been suggested in the last few years. It has been estimated that patients diagnosed with some types of inflammatory bowel disease, such as ulcerative colitis or Crohn’s disease, have up to a 30% increased risk of developing colon cancer. However, there is also evidence showing that the activation of anti-inflammatory pathways, such as the IL-4 receptor-mediated pathway, may favor the development of colon tumors. Using an experimental model of colitis-associated colon cancer (CAC), we found that the decrease in tumor development in global IL4Rα knockout mice (IL4RαKO) was apparently associated with an inflammatory response mediated by the infiltration of M1 macrophages (F480+TLR2+STAT1+) and iNOS expression in colon tissue. However, when we developed mice with a specific deletion of IL4Rα in macrophages (LysMcreIL4Rα−/lox mice) and subjected them to CAC, it was found that despite presenting a large infiltration of M1 macrophages into the colon, these mice were as susceptible to colon-tumorigenesis as WT mice. These data suggest that in the tumor microenvironment the absence of IL4Rα expression on macrophages, as well as the recruitment of M1 macrophages, may not be directly associated with resistance to developing colon tumors. Therefore, it is possible that IL4Rα expression in other cell types, such as colonic epithelial cells, could have an important role in promoting the development of colitis-associated colon tumorigenesis.

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Selective expression of constitutively activated STAT6 in intestinal epithelial cells promotes differentiation of secretory cells and protection against helminths

Cited by 22 publications

References 39 publications

Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation in severe disease

Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation in severe disease

Th2 cell‐derived IL‐4/IL‐13 promote ILC2 accumulation in the lung by ILC2‐intrinsic STAT6 signaling in mice

Recruitment of M1 Macrophages May Not Be Critical for Protection against Colitis-Associated Tumorigenesis

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