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Review
. 2019 Nov 7;10(11):849.
doi: 10.1038/s41419-019-2086-z.

"V体育平台登录" Keep calm: the intestinal barrier at the interface of peace and war

Lester Thoo  1   2 , Mario Noti  1   3 , Philippe Krebs  4
Affiliations
Review

VSports - Keep calm: the intestinal barrier at the interface of peace and war

Lester Thoo et al. Cell Death Dis. .

Abstract

Epithelial barriers have to constantly cope with both harmless and harmful stimuli. The epithelial barrier therefore serves as a dynamic and not static wall to safeguard its proper physiological function while ensuring protection. This is achieved through multiple defence mechanisms involving various cell types - epithelial and non-epithelial - that work in an integrated manner to build protective barriers at mucosal sites. Damage may nevertheless occur, due to pathogens, physical insults or dysregulated immune responses, which trigger a physiologic acute or a pathologic chronic inflammatory cascade. Inflammation is often viewed as a pathological condition, particularly due to the increasing prevalence of chronic inflammatory (intestinal) diseases. However, inflammation is also necessary for wound healing. The aetiology of chronic inflammatory diseases is incompletely understood and identification of the underlying mechanisms would reveal additional therapeutic approaches. Resolution is an active host response to end ongoing inflammation but its relevance is under-appreciated. Currently, most therapies aim at dampening inflammation at damaged mucosal sites, yet these approaches do not efficiently shut down the inflammation process nor repair the epithelial barrier. Therefore, future treatment strategies should also promote the resolution phase. Yet, the task of repairing the barrier can be an arduous endeavour considering its multiple integrated layers of defence - which is advantageous for damage prevention but becomes challenging to repair at multiple levels. In this review, using the intestines as a model epithelial organ and barrier paradigm, we describe the consequences of chronic inflammation and highlight the importance of the mucosae to engage resolving processes to restore epithelial barrier integrity and function VSports手机版. We further discuss the contribution of pre-mRNA alternative splicing to barrier integrity and intestinal homeostasis. Following discussions on current open questions and challenges, we propose a model in which resolution of inflammation represents a key mechanism for the restoration of epithelial integrity and function. .

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"V体育官网" Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Geographical layers of intestinal (colon) defence mechanisms.
The epithelial barrier consists of multiple layers of defence, which function both simultaneously and subsequently with each other. Geographically, from the outside (lumen) towards the inside (lamina propria): (1) the outer most layer consists of mucus which acts as a physical barrier (2) that is further reinforced biochemically with antimicrobial peptides and immunoglobulin A. (3) Intestinal epithelial cells form a single-cell layer of protection which is interspersed with intraepithelial lymphocytes. (4) Within intestinal crypts are intestinal epithelial stem cells, which are key in replenishing the epithelial surface. (5) Beyond the epithelial layer is the lamina propria, which is densely populated with leukocytes that serve to back up the innate immune defences and provide immunological memory against future repeated insults. Note that this graphic does not dictate the order of importance but rather serves to visualise the multiple layers of defence that make up the epithelial barrier. Abbreviations: Immunoglobulin A, IgA; intraepithelial lymphocyte, IEL; intestinal epithelial cell, IEC; intestinal epithelial stem cell, IESC. Figure adapted from stock images provided by Servier (https://smart.servier.com/smart_image/)
Fig. 2
Fig. 2. Damaging and healing properties of inflammation at barrier sites.
a Acute barrier damage induces an inflammatory response, which starts as a localised response to help repair the barrier: (i) Damage and release of alarmins (e.g. IL-33) and (ii) localised inflammatory cytokine release (e.g. IL-6 and TNF) activate tissue myeloid cells to clear harmful noxae and promote IEC proliferation; (iii) the inflammation phase is shadowed by a resolution phase (iv) which successfully shuts down inflammation and permits the restoration of the barrier. b Chronic inflammation induces further barrier damage: (v) If inflammation becomes uncontrolled, this creates a pro-inflammatory microenvironment due to the increased cytokine release and leukocyte infiltration, (vi) increased barrier disruption occurs due to the actions of pro-inflammatory leukocytes leading to (vii) systemic involvement of the immune system and chronic inflammation at the barrier. Abbreviations: Intestinal epithelial cell, IEC; damage-associated molecular patterns, DAMPs; pathogen-associated molecular patterns, PAMPs; interleukin-33, IL-33; interleukin-6, IL-6; tumour necrosis factor, TNF. Figure adapted from stock images provided by Servier (https://smart.servier.com/smart_image/)
Fig. 3
Fig. 3. Combining strategies to target inflammation, resolution and epithelial barrier repair.
a Dampening the inflammatory response in the damaged barrier is critical to allow resolution mechanisms to take place. Current therapeutics for intestinal inflammation (e.g. IBD) utilise anti-inflammatory and/or anti-migratory drugs. b The resolution phase involves conversion of pro-inflammatory lipid mediators such as leukotrienes and prostaglandins into specialised pro-resolution mediators such as resolvins. In addition, other cytokines such as IL-22 and IL-10 help to further dampen inflammatory responses while IL-33 and growth factors such as EGF promote IEC repair. Future therapeutic interventions may foster resolution by using pro-resolving factors or synthesised mimetics. Promotion of IEC repair and maintenance could also be enhanced by targeting specific splicing isoforms or via the application of bacterial-derived metabolites as their specific cellular targets and mode of action become better delineated (c). Combination of anti-inflammatory treatments with therapeutic promotion of resolution and epithelial barrier repair restores a functional barrier to prevent further inflammation. Areas for therapeutic manipulations are indicated by blue text and arrows. Abbreviation: alpha-4 beta-7 integrin, α4β7; epidermal growth factor, EGF; interferon γ, IFNγ; interleukin 6, IL-6; interleukin 10, IL-10; interleukin 22, IL-22; interleukin 33, IL-33; intestinal epithelial cell, IEC; macrophage, Mφ; maresin 1, MaR1; nuclear factor kappa-light-chain-enhancer of activated B cells, NF-κB; omega-3, ω-3; resolvin E1, RvE1; specialised pro-resolving lipid mediators, SPM; tumour necrosis factor, TNF. Figure adapted from stock images provided by Servier (https://smart.servier.com/smart_image/)
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