The IL-23/IL-17 pathway in inflammatory bowel disease

The etiology of inflammatory bowel disease is unknown but available evidence suggests that a deregulated immune response towards the commensal bacterial flora is responsible for intestinal inflammation in genetically predisposed individuals. IL-23 promotes expansion and maintenance of Th17 cells, which secrete the proinflammatory cytokine IL-17 and have been implicated in the pathogenesis of many chronic inflammatory disorders. Recent studies have shown that IL-23 also acts on cells of the innate immune system that can contribute to inflammatory cytokine production and tissue inflammation. A role for the IL-23/IL-17 pathway in the pathogenesis of chronic intestinal inflammation in inflammatory bowel disease has emerged from both animal and human studies. Here we aim to review the recent advances in this rapidly moving field.     

Protein tyrosine phosphatase non-receptor type 2 and inflammatory bowel disease

Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2(PTPN2) with the onset of inflammatory bowel disease(IBD) and other inflammatory disorders. Expression of PTPN2 is enhanced in actively inflamed intestinal tissue featuring a marked up-regulation in intestinal epithelial cells. PTPN2 deficient mice suffer from severe intestinal and systemic inflammation and display aberrant innate and adaptive immune responses. In particular, PTPN2 is involved in the regulation of inflammatory signalling cascades, and critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses, and finally for maintaining intestinal homeostasis. On one hand, dysfunction of PTPN2 has drastic effects on innate host defence mechanisms, including increased secretion of pro-inflammatory cytokines, limited autophagosome formation in response to invading pathogens, and disruption of the intestinal epithelial barrier. On the other hand, PTPN2 function is crucial for controlling adaptive immune functions, by regulating T cell proliferation and differentiation as well as maintaining T cell tolerance. In this way, dysfunction of PTPN2 contributes to the manifestation of IBD. The aim of this review is to present an overview of recent findings on the role of PTPN2 in intestinal homeostasis and the impact of dysfunctional PTPN2 on intestinal inflammation.     

Role of mucosal dendritic cells in inflammatory bowel disease

The gastrointestinal innate and adaptive immune system continuously faces the challenge of potent stimuli from the commensal microflora and food constituents. These local immune responses require a tight control, the outcome of which is in most cases the induction of tolerance. Local T cell immunity is an important compartment of the specif ic intestinal immune system. T cell reactivity is programmed during the initial stage of its activation by professional presenting cells. Mucosal dendritic cells （DCs） are assumed to play key roles in regulating immune responses in the antigenrich gastrointestinal environment. Mucosal DCs are a heterogeneous population that can either initiate （innate and adaptive） immune responses, or control intestinal inflammation and maintain tolerance. Defects in this regulation are supposed to lead to the two major forms of inflammatory bowel disease （IBD）, Crohn＇s disease （CD） and ulcerative colitis （UC）. This review will discuss the emerging role of mucosal DCs in regulating intestinal inflammation and immune responses.     

Role of the Innate Immune System in Acute Viral Myocarditis

Although the adaptive immune system is thought to play an important role in the pathogenesis of viral myocarditis, the role of the innate immune system has not been well defined. To address this deficiency, we employed a unique line of mice that harbor a genomic “knock in” of a mutated TNF gene lacking the AU rich element (TNF^ARE/ARE) that is critical for TNF mRNA stability and translation, in order to examine the contribution of the innate immune system in encephalomyocarditis-induced myocarditis (EMCV). Heterozygous mice (TNF^ARE/+) were infected with 500 plaque-forming units of EMCV. TNF^ARE/+mice had a significantly higher 14-day mortality and myocardial inflammation when compared to littermate control mice. Virologic studies showed that the viral load at 14 days was significantly lower in the hearts of TNF^ARE/+ mice. TNF^ARE/+ mice had an exaggerated proinflammatory cytokine and chemokine response in the heart following EMCV infection. Modulation of the innate immune response in TNF^ARE/+ mice by the late administration of prednisolone resulted in a significant improvement in survival and decreased cardiac inflammation, whereas early administration of prednisolone resulted in a blunted innate response and increased mortality in littermate control mice. Viewed together, these data suggest that the duration and degree of activation of the innate immune system plays a critical role in determining host outcomes in experimental viral myocarditis. C.-H. Huang and J.G. Vallejo have equally contributed to this work.     

Paneth cell defensins and the regulation of the microbiome

Recently, our laboratory demonstrated that Paneth cell defensins, innate antimicrobial peptides that contribute to mucosal host defense, are able to regulate the composition of the intestinal bacterial microbiome. Using complementary mouse models of defensin deficiency (MMP7-/-) and surplus (HD5+/+), we noted defensin-dependent reciprocal shifts in the dominant bacterial species of the small intestine, without changes in total bacterial numbers. In addition, mice that expressed HD5 showed a significant loss of segemented filamentous bacteria (SFB), resulting in reduced numbers of Th17 cells in the lamina propria. This data showed a novel role for PC defensins in intestinal homeostasis, by regulation of the small intestinal microbiome. The microbiome plays an essential role in mediating host physiology, metabolism, and immune response. The ability of PC defensins to regulate the composition of the biome suggests a much broader importance of these innate immune effectors than previously considered. In this addendum, the role of PC defensins in the regulation of the intestinal microbiome is reviewed, and discussed in the context of recent evidence that highlights the important role of PCs and defensins in the pathophysiology of inflammatory bowel disease.     

Heme oxygenase-1 and carbon monoxide regulate intestinal homeostasis and mucosal immune responses to the enteric microbiota

Heme oxygenase-1 (HO-1) and its enzymatic by-product carbon monoxide (CO) have emerged as important regulators of acute and chronic inflammation. Mechanisms underlying their anti-inflammatory effects are only partially understood. In this addendum, we summarize current understanding of the role of the HO-1/CO pathway in regulation of intestinal inflammation with a focus on innate immune function. In particular, we highlight our recent findings that HO-1 and CO ameliorate intestinal inflammation through promotion of bacterial clearance. Our work and that of many others support further investigation of this global homeostatic pathway in the human inflammatory bowel diseases (IBDs).     

Heme oxygenase-1 and carbon monoxide regulate intestinal homeostasis and mucosal immune responses to the enteric microbiota

Heme oxygenase-1 (HO-1) and its enzymatic by-product carbon monoxide (CO) have emerged as important regulators of acute and chronic inflammation. Mechanisms underlying their anti-inflammatory effects are only partially understood. In this addendum, we summarize current understanding of the role of the HO-1/CO pathway in regulation of intestinal inflammation with a focus on innate immune function. In particular, we highlight our recent findings that HO-1 and CO ameliorate intestinal inflammation through promotion of bacterial clearance. Our work and that of many others support further investigation of this global homeostatic pathway in the human inflammatory bowel diseases (IBDs).     

Current view of the immunopathogenesis in inflammatory bowel disease and its implications for therapy

Although the aetiology of inflammatory bowel disease （IBD） remains unknown, the pathogenesis is gradually being unravelled, seeming to be the result of a combination of environmental, genetic, and immunological factors in which an uncontrolled immune response within the intestinal lumen leads to inflammation in genetically predisposed individuals. Multifactorial evidence suggests that a defect of innate immune response to microbial agents is involved in IBD. This editorial outlines the immunopathogenesis of IBD and their current and future therapy. We present IBD as a result of dysregulated mucosal response in the intestinal wall facilitated by defects in epithelial barrier function and the mucosal immune system with excessive production of cytokines growth factors, adhesion molecules, and reactive oxygen metabolites, resulting in tissue injury. Established and evolving therapies are discussed in the second part of this editorial and at the end of this section we review new therapies to modulate the immune system in patients with IBD.     

Therapeutic approaches targeting intestinal microflora in inflammatory bowel disease

Inflammatory bowel diseases, ulcerative colitis, and Crohn's disease, are chronic intestinal disorders of unknown etiology in which in genetically susceptible individuals, the mucosal immune system shows an aberrant response towards commensal bacteria. The gastrointestinal tract has developed ingenious mechanisms to coexist with its autologous microflora, but rapidly responds to invading pathogens and then returns to homeostasis with its commensal bacteria after the pathogenic infection is cleared. In case of disruption of this tightly-regulated homeostasis, chronic intestinal inflammation may be induced. Previous studies showed that some commensal bacteria are detrimental while others have either no influence or have a protective action. In addition, each host has a genetically determined response to detrimental and protective bacterial species. These suggest that therapeutic manipulation of imbalance of microflora can influence health and disease. This review focuses on new insights into the role of commensal bacteria in gut health and disease, and presents recent findings in innate and adaptive immune interactions. Therapeutic approaches to modulate balance of intestinal microflora and their potential mechanisms of action are also discussed.     

Role of bacteria in experimental colitis

Epidemiology suggests some relationship between the establishment of the gut flora and the risk of developing inflammatory bowel disease. Unrestrained activation of the immune system against commensal bacteria appears to be responsible for the chronicity of these diseases. In animal models, broad-spectrum antibiotics reduce the bacterial load and militate against intestinal inflammation. Several bacterial species found in of the common microflora, including anaerobes, are able to invade the colonic wall when there is dysfunction of the colonic mucosal barrier. Most aerobes provoke focal areas of acute inflammation, but some anaerobes in the predominant flora induce diffuse a fibrogenic transmural response. Current research aims to identify the probiotics that might act against these bacteria. Colonization with specific probiotic strains, including a bacterium genetically engineered to secrete interleukin-10, prevents spontaneous colitis in susceptible mice. Certain lactobacilli exhibit anti-inflammatory properties naturally, i.e. without previous genetic manipulation. Prebiotics may increase colonization by lactobacilli and can prevent mucosal inflammation. Modulation of the gut flora with probiotics may prove useful in the prevention and control of inflammatory bowel diseases.     

Role of microRNAs in the immune system,inflammation and cancer

MicroRNAs,a key class of gene expression regulators,have emerged as crucial players in various biological processes such as cellular proliferation and differentiation,development and apoptosis.In addition,microRNAs are coming to light as crucial regulators of innate and adaptive immune responses,and their abnormal expression and/or function in the immune system have been linked to multiple human diseases including inflammatory disorders,such as inflammatory bowel disease,and cancers.In this review,we discuss our current understanding of microRNAs with a focus on their role and mode of action in regulating the immune system during inflammation and carcinogenesis.     

Innate and adaptive immunity in inflammatory bowel disease

Inflammatory bowel diseases are the consequence of a dysregulated mucosal immune system. The mucosal immune system consists of two arms, innate and adaptive immunity, that have been studied separately for a long time. Functional studies from in vivo models of intestinal inflammation as well as results from genome-wide association studies strongly suggest a crossregulation of both arms. The present review will illustrate this interaction by selecting examples from innate immunity and adaptive immunity, and their direct impact on each other. Broadening our view by focusing on the cross-regulated areas of the mucosal immune system will not only facilitate our understanding of disease, but furthermore will allow identification of future therapeutic targets.     

Biologic therapy of inflammatory bowel disease

Biological therapies in inflammatory bowel disease reflect the exponential advancement in understanding the human intestinal immune system and particularly the biology of intestinal inflammation during the past decade. The better understanding of the mechanisms of inflammatory bowel disease has evolved from desriptive clinical data and genetically engineered animal models. It led to great interest in the evaluation of a variety of new therapeutic agents with novel actions. This review will discuss the mechanisms of biologicals (antibodies against pro-inflammatory cytokines, T cell antibodies, anti-inflammtory cytokines, adhesion molecule blockers, growth factors, hormones, colony stimulating factors, fusion proteins, anti-sense oligonucleotides, trefoil peptides, immunostimulatory [ISS] DNA) used in the treatment of inflammatory bowel disease and summarizes the available data on established biologic therapies as well as investigational agents and briefly touch on probiotics. Based on the data discussed, it seems that biologicals will play an important role in managing inflammatory bowel disease in the near future.     

Toll-like receptors in inflammatory bowel disease-stepping into uncharted territory

Ulcerative colitis and Crohn＇s disease are chronic relapsing-remitting inflammatory processes of the intestinal tract. The etiology of these diseases is currently unknown. However, inflammation is hypothesized to result from inappropriate activation of mucosal immunity by luminal antigens in genetically susceptible individuals. Toll-like receptors （TLRs） are a family of transmembrane proteins that act as microbial pattern recognition receptors. They are crucial initiators of innate immune responses. The role of TLRs in the pathogenesis of inflammatory bowel disease （IBD） has not been fully elucidated. In this review, we aim to analyze the available data connecting individual TLRs to intestinal inflammation and IBD.     

Paneth cell defensins and the regulation of the microbiome: détente at mucosal surfaces

Recently, our laboratory demonstrated that Paneth cell defensins, innate antimicrobial peptides that contribute to mucosal host defense, are able to regulate the composition of the intestinal bacterial microbiome. Using complementary mouse models of defensin deficiency (MMP7(-/-)) and surplus (HD5(+/+)), we noted defensin-dependent reciprocal shifts in the dominant bacterial species of the small intestine, without changes in total bacterial numbers. In addition, mice that expressed HD5 showed a significant loss of segemented filamentous bacteria (SFB), resulting in reduced numbers of Th17 cells in the lamina propria. This data showed a novel role for PC defensins in intestinal homeostasis, by regulation of the small intestinal microbiome. The microbiome plays an essential role in mediating host physiology, metabolism and immune response. The ability of PC defensins to regulate the composition of the biome suggests a much broader importance of these innate immune effectors than previously considered. In this addendum, the role of PC defensins in the regulation of the intestinal microbiome is reviewed, and discussed in the context of recent evidence that highlights the important role of PCs and defensins in the pathophysiology of inflammatory bowel disease.