Resistin-like molecule β is a bactericidal protein that promotes spatial segregation of the microbiota and the colonic epithelium

Propheter, Daniel C.; Chara, Andrew L.; Harris, Tamia A.; Ruhn, Kelly A.; Hooper, Lora V.

doi:10.1073/pnas.1711395114

Cited by 139 publications

(126 citation statements)

References 46 publications

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“…Both cytokines are known to induce goblet cells, and IL-22 is also important for type 2 immunity-driven goblet cell hyperplasia in vivo (Turner, Stockinger, and Helmby 2013). Additionally, the goblet-cell effector RELM-beta is critical for resistance against both bacterial and helminth infections (Artis et al 2004; Bergstrom et al 2015; Propheter et al 2017). We hypothesize that the difference is related to the type of immune response.…”

Section: Discussionmentioning

confidence: 99%

Developmental pathways regulate cytokine-driven effector and feedback responses in the intestinal epithelium

Lindholm

Parmar

Drurey

et al. 2020

Preprint

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12The intestinal tract is a common site for infection, and it relies on an appropriate immune response to 13 defend against pathogens. The intestinal epithelium has an important role in effector responses, which 14 is coordinated by immune-type specific cytokines. It is incompletely understood how cytokines drive 15 epithelial responses. Here, using organoid-cytokine co-cultures, we provide a comprehensive analysis 16 of how key cytokines affect the intestinal epithelium, and relate this to in vivo infection models. We 17 use imaging, based on a convolutional neural network, and transcriptomic analysis to reveal that 18 cytokines use developmental pathways to define intestinal epithelial effector responses. For example, 19 we find IL-22 and IL-13 dichotomously induce goblet cells, in which only IL-13 driven goblet cells are 20 associated with NOTCH signaling. We further show that IL-13 induces BMP signalling to act as a 21 negative feedback loop in IL-13 induced tuft cell hyperplasia, an important aspect of type 2 immunity. 22Together, we show that targeting developmental pathways may be a useful tool to tailor epithelial 23 effector responses that are necessary for immunity to infection. 24 1 Infections of the gastrointestinal tract remain one of the leading health issues worldwide (Kirk et al. 2015). The 26 ability to clear infections relies on the capacity of the immune system to mount an appropriate response. Immune 27 responses can be divided into 3 types. Broadly; type 1 responses are launched against intracellular pathogens 28 such as bacteria and viruses and are associated with the cytokine interferon gamma (IFNγ), type 2 responses are 29 generated to fight off parasitic infections and are driven by interleukin (IL)-4 and IL-13, and finally, type 3 responses 30 are mounted against extracellular pathogens such as bacteria and are associated with IL-22 and IL-17 (Kara et al. 31 2014; Raphael et al. 2015). 32 In addition to defining the immune landscape, cytokines directly affect intestinal epithelial cells (IECs) to drive 33 immune-type specific effector responses (Biton et al. 2018). The intestinal epithelium consists of a single layer of 34 cells and is responsible both for taking up nutrients as well as providing a protective barrier. One of the hallmarks 35 of IECs is their rapid turnover (3-5 days), which allows for prompt cellular responses, for example, to expand goblet 36 cells which can produce protective mucus. This plasticity of IECs makes them particularly well-suited to defend 37 against pathogens (Tetteh, Farin, and Clevers 2015). In addition to responding to immune cues, the epithelium 38 can also be involved in tailoring immune responses. For example, tuft cells, which are important for defending 39 against parasitic helminths, are the main source of IL-25 to control ILC2 populations both in homeostasis and upon 40 helminth infection (Gerbe et al. 2016; Howitt et al. 2016; Moltke et al. 2016). As tuft cells rapidly expand upon 41 exposure to type 2 cytokines, they exemplify both how th...

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Section: Discussionmentioning

confidence: 99%

Developmental pathways regulate cytokine-driven effector and feedback responses in the intestinal epithelium

Lindholm

Parmar

Drurey

et al. 2020

Preprint

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“…21 Finally, RELMb is a bactericidal protein that promotes spatial segregation of the microbiota and the colonic epithelium. 23 Therefore, RELMb plays an important role in anti-inflammatory regulation in the local immunity and infection of the intestinal tract. So far, however, no literature has reported the changes and clinical significance of RELMb in neonatal NEC.…”

Section: Discussionmentioning

confidence: 99%

Early diagnosis of necrotizing enterocolitis by plasma RELMβ and thrombocytopenia in preterm infants: A pilot study

Luo

et al. 2019

Pediatrics & Neonatology

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Pediatrics and Neonatology (2019) 60, 447e452 significant difference was found in plasma Resistin levels between two groups (P > 0.05). If platelet level was less than 157 Â 10 9 /L, the sensitivity and specificity were 69.34% and 82.87%, respectively. Interestingly, the combination of RELMb and thrombocytopenia increased sensitivity and specificity to 82.89% and 93.21%, respectively. Conclusion: The combination of RELMb and thrombocytopenia was a reliable biomarker for the early diagnosis of NEC in this study with 82.89% sensitivity and 93.21% specificity, respectively.

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“…26 To protect against this, GCs secrete RELM-β along with mucins. RELM-β has direct bactericidal properties, killing commensal bacteria and pathogens that penetrate into the mucus layer [27][28][29] and targeting helminths for expulsion. 10 Other components found in the inner layer of the mucus, like the zymogen granulae protein 16 (ZG16) aggregates bacteria, preventing adherence of the bacteria to the epithelium.…”

Section: Limiting Encounters With Luminal Microbes Through Barrier Mamentioning

confidence: 99%

Goblet cells: multifaceted players in immunity at mucosal surfaces

2018

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Goblet cells (GCs) are specialized epithelial cells that line multiple mucosal surfaces and have a well-appreciated role in barrier maintenance through the secretion of mucus. Moreover, GCs secrete anti-microbial proteins, chemokines, and cytokines demonstrating functions in innate immunity beyond barrier maintenance. Recently it was appreciated that GCs can form goblet cell-associated antigen passages (GAPs) and deliver luminal substances to underlying lamina propria (LP) antigen-presenting cells (APCs) in a manner capable of inducing adaptive immune responses. GCs at other mucosal surfaces share characteristics with the GAP forming intestinal GCs, suggesting that GAP formation may not be restricted to the gut, and that GCs may perform this gatekeeper function at other mucosal surfaces. Here we review observations of how GCs contribute to immunity at mucosal surfaces through barrier maintenance, the delivery of luminal substances to APCs, interactions with APCs, and secretion of factors modulating immune responses.

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Resistin-like molecule β is a bactericidal protein that promotes spatial segregation of the microbiota and the colonic epithelium

Cited by 139 publications

References 46 publications

Developmental pathways regulate cytokine-driven effector and feedback responses in the intestinal epithelium

Developmental pathways regulate cytokine-driven effector and feedback responses in the intestinal epithelium

Early diagnosis of necrotizing enterocolitis by plasma RELMβ and thrombocytopenia in preterm infants: A pilot study

Goblet cells: multifaceted players in immunity at mucosal surfaces

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