Atopic dermatitis (AD) is a chronic inflammatory skin disease of increasing prevalence, especially in industrialized countries. Roughly 25% of the children and 1%-3% of adults are affected. Although significant progress has been made in the understanding of the pathogenesis of AD, many aspects remain poorly understood. Moreover, there is a pressing need for improved therapeutic options. Studies to elucidate the pathophysiological pathways of AD and to identify novel therapeutic targets over the last few decades have been conducted almost exclusively in animal models. However, in vitro approaches such as 3D skin disease models have recently emerged due to an increasing awareness of distinct interspecies-related differences that hamper the effective translation of results from animal models to humans. In addition, there is growing political and social pressure to develop alternatives to animal models according to the 3Rs principle (reduction, refinement and replacement of animal models). K E Y W O R D S3R approach, atopic dermatitis, preclinical dermatology, skin equivalents, skin model
Background and Aims Uncontrolled activation of intestinal mononuclear phagocytes (MNPs) drives chronic inflammation in inflammatory bowel disease (IBD). Triggering receptor expressed on myeloid cells 1 (TREM-1) has been implicated in IBD pathogenesis. However, the role of TREM-1 + cell subsets in driving IBD pathology, and the link with clinical parameters, are not understood. We investigated TREM-1 expression in human intestinal MNP subsets and examined blocking TREM-1 as a potential IBD therapy. Methods TREM-1 gene expression was analysed in intestinal mucosa, enriched epithelial and lamina propria (LP) layers and purified cells from controls and IBD patients. TREM-1 protein on immune cells was assessed by flow cytometry and immunofluorescence microscopy. Blood monocyte activation was examined by large-scale gene expression using a TREM-1 agonist or LP conditioned media (LP-CM) from patients in the presence or absence of TREM-1 and TNF antagonist antibodies. Results TREM-1 gene expression increases in intestinal mucosa from IBD patients and correlates with the disease score. TREM-1 + cells, which are mainly immature macrophages and CD11b + granulocytes, increase among LP cells from Crohn’s patients and their frequency correlates with inflammatory molecules in LP-CM. LP-CM from Crohn’s patients induces an inflammatory transcriptome in blood monocytes, including increased IL-6 expression, which is reduced by simultaneous blocking of TREM-1 and TNF. Conclusions High intestinal TREM-1 expression, reflecting a high frequency of TREM-1 + immature macrophages and TREM-1 +CD11b + granulocytes, is linked to the deleterious inflammatory microenvironment in IBD patients. Therefore, blocking the TREM-1 pathway, especially simultaneously with anti-TNF therapy, has potential as a new IBD therapy.
Initial colonizing bacteria play a critical role in completing the development of the immune system in the gastrointestinal tract of infants. Yet, the interaction of colonizing bacterial organisms with the developing human intestine favors inflammation over immune homeostasis. This characteristic of bacterial-intestinal interaction partially contributes to the pathogenesis of necrotizing enterocolitis (NEC), a devastating premature infant intestinal inflammatory disease. However, paradoxically some unique pioneer bacteria (initial colonizing species) have been shown to have a beneficial effect on the homeostasis of the immature intestine and the prevention of inflammation. We have reported that one such pioneer bacterium, Bacteroides fragilis ( B. fragilis), and its surface component polysaccharide A (PSA) inhibit IL-1β-induced inflammation in a human primary fetal small intestinal cell line (H4 cells). In this study, using transcription profiling of H4 cellular RNA after pretreatment with or without PSA before an inflammatory stimulation of IL-1β, we have begun to further determine the cellular mechanism for anti-inflammation. We show that a developmentally regulated gene, zona pellucida protein 4 ( ZP4), is uniquely elevated after IL-1β stimulation and reduced with PSA exposure. ZP4 was known as a sperm receptor-mediating species-specific binding protein in the initial life of mammals. However, its intestinal epithelial function is unclear. We found that ZP4 is a developmentally regulated gene involved with immune function and regulated by both Toll-like receptor 2 and 4. Knockdown of ZP4-affected PSA inhibited IL-8 mRNA expression in response to IL-1β. This represents an initial study of ZP4 innate immune function in immature enterocytes. This study may lead to new opportunity for efficient treatment of NEC. NEW & NOTEWORTHY This study extends previous observations to define the cellular mechanisms of polysaccharide A-induced anti-inflammation in immature enterocytes using transcription profiling of enterocyte genes after preexposure to polysaccharide A before an inflammatory stimulus with IL-1β.
Numerous studies point to the important role of probiotic bacteria in gastrointestinal health. Probiotics act through mechanisms affecting enteric pathogens, epithelial barrier function, immune signaling, and conditioning of indigenous microbiota. Once administered, probiotics reach the gastrointestinal tract and interact with the host through bacterial surface molecules, here called adhesion factors, which are either strain- or specie-specific. Probiotic adhesion, through structural adhesion factors, is a mechanism that facilitates persistence within the gastrointestinal tract and triggers the initial host responses. Thus, an understanding of specific probiotic adhesion mechanisms could predict how specific probiotic strains elicit benefits and the potential of adherence factors as a proxy to predict probiotic function. This review summarizes the present understanding of probiotic adherence in the gastrointestinal tract. It highlights the bacterial adhesion structure types, their molecular communication with the host and the consequent impact on intestinal diseases in both adult and pediatric populations. Finally, we discuss knockout/isolation studies as direct evidence for adhesion factors conferring anti-inflammatory and pathogen inhibition properties to a probiotic. What is known : Probiotics can be used to treat clinical conditions. Probiotics improve dysbiosis and symptoms. Clinical trials may not confirm in vitro and animal studies. What is new : Adhesion structures may be important for probiotic function. Need to systematically determine physical characteristics of probiotics before selecting for clinical trials. Probiotics may be genetically engineered to add to clinical efficacy.
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