scholarly journals Keep calm: the intestinal barrier at the interface of peace and war

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Lester Thoo ◽  
Mario Noti ◽  
Philippe Krebs
Keyword(s):  
Inflammatory Diseases ◽  
Pathological Condition ◽  
Treatment Strategies ◽  
Intestinal Barrier ◽  
Cell Types ◽  
Epithelial Barrier ◽  
Barrier Integrity ◽  
Epithelial Barriers ◽  
Underlying Mechanisms ◽  
And Function

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. 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.

Molecular mechanisms of the glucocorticoid receptor in steroid therapy – lessons from transgenic mice

2012 ◽  
Vol 3 (3) ◽  
pp. 241-253 ◽  
Author(s):  
Sabine Hübner ◽  
Jan Tuckermann
Keyword(s):  
Side Effects ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Pathological Condition ◽  
Cell Types ◽  
Therapeutic Effects ◽  
Gene Promoters ◽  
Inflammatory Conditions ◽  
Anti Inflammatory ◽  
And Function

AbstractGlucocorticoids (GCs) are potent anti-inflammatory agents that are used to treat chronic inflammatory diseases, allergic conditions, and some cancers. However, their therapeutic effects are hampered by severe side effects, such as muscle weakness, insulin resistance, fat redistribution, and osteoporosis. GCs act on many cell types that express the GC receptor (GR) via several modes of action. One of them includes GR homodimers recognizing binding sequences in the DNA of gene promoters. Another mode involves the modulation of other DNA-bound transcription factors via dimer-independent mechanisms. To what extent these mechanisms contribute to GC-mediated effects is currently being elucidated from analyses of mice with conditional and function-selective mutations of the GR and is summarized in this review. Whether GR homodimerization or its monomer activity is decisive in the therapeutic effectiveness and associated side effects of GCs for the treatment of inflammatory conditions depends on the type of the pathological condition. Thus, the classic criterion for selective GR modulators, discrimination between GR dimer- and GR monomer-dependent protein-protein interaction, will not help in any condition to avoid side effects and maintain anti-inflammatory activity. Rather, novel criteria for selective GR modulators have to be defined that take into consideration the tissue-specific mechanisms of the GR to achieve optimized anti-inflammatory therapies with reduced side effects. In the case of avoiding osteoporosis as a side effect, a first example of such optimized compounds can be provided.

Effects of human rhinovirus on epithelial barrier integrity and function in children with asthma

2018 ◽  
Vol 48 (5) ◽  
pp. 513-524 ◽  
Author(s):  
K. Looi ◽  
A. G. Buckley ◽  
P. J. Rigby ◽  
L. W. Garratt ◽  
T. Iosifidis ◽  
...  
Keyword(s):  
Human Rhinovirus ◽  
Epithelial Barrier ◽  
Barrier Integrity ◽  
Children With Asthma ◽  
And Function

scholarly journals Betaine attenuates LPS-induced downregulation of Occludin and Claudin-1 and restores intestinal barrier function

2020 ◽  
Author(s):  
Jingtao Wu ◽  
Caimei He ◽  
Jie Bu ◽  
Yue Luo ◽  
Shuyuan Yang ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intestinal Barrier ◽  
Protective Role ◽  
Vital Role ◽  
Inflammatory Factors ◽  
Intestinal Barrier Function ◽  
Epithelial Barrier ◽  
Epithelial Barriers ◽  
Vitro Model

Abstract Background：The intestinal epithelial barrier, which works as the first line of defense between the luminal environment and the host, once destroyed, it will cause serious inflammation or other intestinal diseases. Tight junctions (TJs) play a vital role to maintain the integrity of the epithelial barrier. Lipopolysaccharide (LPS), one of the most important inflammatory factors will downregulate specific TJ proteins including Occludin and Claudin-1 and impair integrity of the epithelial barrier. Betaine has excellent anti-inflammatory activity but whether betaine has any effect on TJ proteins, particularly on LPS-induced dysfunction of epithelial barriers remains unknown. The purpose of this study is to explore the pharmacological effect of betaine on improving intestinal barrier function represented by TJ proteins. Intestinal porcine epithelial cells (IPEC-J2) were used as an in vitro model. Results: The results demonstrated that betaine enhanced the expression of TJ proteins while LPS (1µg/mL) downregulates the expression of these proteins. Furthermore, betaine attenuates LPS-induced decreases of TJ proteins both shown by Western blot (WB) and Reverse transcription- polymerase chain reaction (RT-PCR). The immunofluorescent images consistently revealed that LPS induced the disruption of TJ protein Claudin-1 and reduced its expression while betaine could reverse these alterations. Similar protective role of betaine on intestinal barrier function was observed by transepithelial electrical resistance (TEER) approach. Conclusion: In conclusion, our research demonstrated that betaine attenuated LPS-induced downregulation of Occludin and Claudin-1 and restored the intestinal barrier function.

Role of Gut Microbiota in Multiple Sclerosis and Potential Therapeutic Implications

2021 ◽  
Vol 19 ◽  
Author(s):  
Xu Wang ◽  
Zhen Liang ◽  
Shengnan Wang ◽  
Di Ma ◽  
Mingqin Zhu ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Gut Microbiota ◽  
Demyelinating Disease ◽  
Inflammatory Diseases ◽  
Intestinal Barrier ◽  
Autoimmune Response ◽  
Therapeutic Implications ◽  
The Central Nervous System ◽  
Underlying Mechanisms

: The role of gut microbiota in health and diseases has been receiving increased attention recently. Emerging evidence from previous studies on the gut-microbiota-brain axis highlighted the importance of gut microbiota in neurological disorders. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) resulting from T-cell-driven, myelin-directed autoimmunity. The dysbiosis of gut microbiota in MS patients has been reported in published research studies, indicating that gut microbiota plays an important role in the pathogenesis of MS. Gut microbiota has also been reported to influence the initiation of disease and severity of experimental autoimmune encephalomyelitis, which is the animal model of MS. However, the underlying mechanisms of gut microbiota involvement in the pathogenesis of MS remain unclear. Therefore, in this review, we summerized the potential mechanisms for gut microbiota involvement in the pathogenesis of MS, including increasing the permeability of the intestinal barrier, initiating an autoimmune response, disrupting the blood-brain barrier integrity, and contributing to chronic inflammation. The possibility for gut microbiota as a target for MS therapy has also been discussed. This review provides new insight into understanding the role of gut microbiota in neurological and inflammatory diseases.

scholarly journals Resolution of inflammation in immune and nonimmune cells by interleukin-19

2020 ◽  
Vol 319 (3) ◽  
pp. C457-C464
Author(s):  
Tani Leigh ◽  
Rosario G. Scalia ◽  
Michael V. Autieri
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Sterile Inflammation ◽  
Compensatory Mechanism ◽  
Compensatory Mechanisms ◽  
Resolution Of Inflammation ◽  
Inflammatory Stimuli ◽  
And Function ◽  
Different Cell Types

The inflammatory response is a complex, tightly regulated process activated by tissue wounding, foreign body invasion, and sterile inflammation. Over the decades, great progress has been made to advance our understanding of this process. One often overlooked aspect of inflammation is its sequel: resolution. We know that dysregulated resolution often results in numerous chronic degenerative diseases such as arthritis, cancer, and asthma. However, identification of components and mechanisms of resolving pathways lags behind those of proinflammatory processes, yet represents overlooked therapeutic opportunities. One approach is identification of endogenous, negative compensatory mechanisms, which are activated in response to inflammation for the purpose of resolution of that inflammatory stimuli. This review will focus on literature that describes expression and function of interleukin-19, a proposed anti-inflammatory cytokine, in numerous inflammatory diseases. The literature concerning IL-19 is complex, context-dependent, and often contradictory. The expression and function of IL-19 in the inflammatory response are in no way settled. We will attempt to clarify the role that this interesting and understudied cytokine plays in resolution of inflammation and discuss its mechanisms of action in different cell types. We will present a hypothesis that endogenous IL-19 expression in response to inflammatory stimuli is a cellular compensatory mechanism to dampen inflammation. We further present studies suggesting that while endogenously expressed IL-19 may be a response to inflammation, pharmacological levels may be necessary to effectively resolve the inflammatory cascade.

scholarly journals Editorial: Loss of Epithelial Barrier Integrity in Inflammatory Diseases: Cellular Mediators and Therapeutic Targets

2021 ◽  
Vol 8 ◽  
Author(s):  
Carl Weidinger ◽  
Susanne M. Krug ◽  
Caroline Voskens ◽  
Alexander R. Moschen ◽  
Imke Atreya
Keyword(s):  
Inflammatory Diseases ◽  
Therapeutic Targets ◽  
Epithelial Barrier ◽  
Barrier Integrity ◽  
Cellular Mediators

scholarly journals IL-33-induced alterations in murine intestinal function and cytokine responses are MyD88, STAT6, and IL-13 dependent

2013 ◽  
Vol 304 (4) ◽  
pp. G381-G389 ◽  
Author(s):  
Zhonghan Yang ◽  
Rex Sun ◽  
Viktoriya Grinchuk ◽  
Joan Antoni Fernandez Blanco ◽  
Luigi Notari ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Inflammatory Diseases ◽  
Biological Activities ◽  
Alternative Activation ◽  
Intestinal Immunity ◽  
Intestinal Function ◽  
Mucosal Permeability ◽  
Underlying Mechanisms ◽  
And Function

IL-33 is a recently identified cytokine member of the IL-1 family. The biological activities of IL-33 are associated with promotion of Th2 and inhibition of Th1/Th17 immune responses. Exogenous IL-33 induces a typical “type 2” immune response in the gastrointestinal tract, yet the underlying mechanisms remain to be fully elucidated. In addition, the role of IL-33 in the regulation of gastrointestinal function is not known. The present study investigated IL-33-dependent intestinal immunity and function in mice. Exogenous IL-33 induced a polarized type 2 cytokine response in the intestine that was entirely MyD88 dependent but STAT6 and IL-13 independent. Mice injected with recombinant IL-33 exhibited intestinal smooth muscle hypercontractility, decreased epithelial responses to acetylcholine and glucose, and increased mucosal permeability. IL-33 effects on intestinal epithelial function were STAT6 dependent, and both IL-4 and IL-13 appeared to play a role. The effects on smooth muscle function, however, were attributable to both STAT6-dependent and -independent mechanisms. In addition, IL-13 induction of insulin-like growth factor-1 was implicated in IL-33-induced smooth muscle hypertrophy. Finally, alternative activation of macrophages induced by IL-33 revealed a novel pathway that is IL-4, IL-13, and STAT6 independent. Thus manipulating IL-33 or related signaling pathways represents a potential therapeutic strategy for treating inflammatory diseases associated with dysregulated intestinal function.

scholarly journals Matrix metalloproteinase 13 modulates intestinal epithelial barrier integrity in inflammatory diseases by activating TNF

2013 ◽  
Vol 5 (7) ◽  
pp. 1000-1016 ◽  
Author(s):  
Roosmarijn E. Vandenbroucke ◽  
Eline Dejonckheere ◽  
Filip Van Hauwermeiren ◽  
Sofie Lodens ◽  
Riet De Rycke ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Inflammatory Diseases ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Intestinal Epithelial Barrier ◽  
Barrier Integrity ◽  
Matrix Metalloproteinase 13

scholarly journals The Role of Regulatory T Cells in the Regulation of Upper Airway Inflammation

2017 ◽  
Vol 31 (6) ◽  
pp. 345-351 ◽  
Author(s):  
Charlie Palmer ◽  
Jennifer K. Mulligan ◽  
Sarah E. Smith ◽  
Carl Atkinson
Keyword(s):  
Cytokine Production ◽  
Inflammatory Diseases ◽  
Upper Airway ◽  
Cell Types ◽  
Inflammatory Cytokine Production ◽  
And Function ◽  
Immunologic Profile ◽  
Type 2 Inflammation

Allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP) are inflammatory diseases of the upper airway, with a similar immunologic profile, characterized by aberrant and persistent type 2 inflammation. One cell population that has been identified as altered in both disease types is regulatory T cell (Treg). Tregs have the capacity to modulate T-effector function and suppress inflammatory cytokine production in a broad range of cell types. Given the ability of Tregs to control inflammation, the role of Tregs in respiratory diseases has attracted much attention. As discussed in this article, alterations in the Treg numbers and function, or both, have been identified in AR and CRSwNP, although much of the data is conflicting. Here, we explored what is known and, in many cases, unknown about the mechanisms by which Tregs differentiate and function, and how these functions can be controlled in the mucosal microenvironment. By gaining a greater understanding of these processes, it may be possible to harness the natural immunosuppressive activity of Tregs to ameliorate the chronic inflammation associated with AR and CRSwNP.

scholarly journals Characterization of a Human In Vitro Intestinal Model for the Hazard Assessment of Nanomaterials Used in Cancer Immunotherapy

2021 ◽  
Vol 11 (5) ◽  
pp. 2113
Author(s):  
Matthew Gibb ◽  
Sahar H. Pradhan ◽  
Marina R. Mulenos ◽  
Henry Lujan ◽  
James Liu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Microscopic Analysis ◽  
Cell Types ◽  
Seeding Density ◽  
Animal Testing ◽  
Barrier Integrity ◽  
International Agencies ◽  
Culture Models ◽  
And Function

There is momentum in biomedical research to improve the structure and function of in vitro intestinal models that better represent human biology. To build a more comprehensive model, three human cell-types were co-cultured and characterized: i.e., HT29-MTX (intestinal mucous-producing goblet cells), Caco-2 (colon epithelial cells), and Raji B (lymphocytes). Raji B cells transformed a subpopulation of Caco-2 epithelial cells into phagocytic and transcytotic immune-supporting microfold cells (M-cells). A suite of bioassays was implemented to investigate steady-state barrier integrity and cellular communication. The model demonstrated a potentiating effect in metabolism and pro-inflammatory markers. Barrier integrity and cell seeding density seem to play a role in the reliability of endpoint readouts. Microscopic analysis elucidated the importance of multi-cell biomimicry. The data show that monocultures do not have the same characteristics inherent to triple cell culture models. Multiple cell types in an in vitro model produce a better representation of an intact organ and aid in the ability to assess immunomodulatory effects of nanomaterials designed for cancer theranostics after ingestion. As many national and international agencies have stressed, there is a critical need to improve alternative-to-animal strategies for pharmaceuticals in an effort to reduce animal testing.

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