A role for IL-22 in the relationship between intestinal helminths,gut microbiota and mucosal immunity

The intestinal tract is home to nematodes as well as commensal bacteria (microbiota), which have coevolved with the mammalian host. The mucosal immune system must balance between an appropriate response to dangerous pathogens and an inappropriate response to commensal microbiota that may breach the epithelial barrier, in order to maintain intestinal homeostasis. IL-22 has been shown to play a critical role in maintaining barrier homeostasis against intestinal pathogens and commensal bacteria. Here we review the advances in our understanding of the role of IL-22 in helminth infections, as well as in response to commensal and pathogenic bacteria of the intestinal tract. We then consider the relationship between intestinal helminths and gut microbiota and hypothesize that this relationship may explain how helminths may improve symptoms of inflammatory bowel diseases. We propose that by inducing an immune response that includes IL-22, intestinal helminths may enhance the mucosal barrier function of the intestinal epithelium. This may restore the mucosal microbiota populations from dysbiosis associated with colitis and improve intestinal homeostasis.     

Mucosal immunity and vaccine development

Mucosae constitute the major entry for most microbial pathogens but also innocuous antigens derived from ingested food, airborne matter or commensal bacteria. A large and highly specialized innate and adaptative mucosal immune system protects the mucosal surfaces and the body interior from potential injuries from the environment. The mucosal immune system has developed a variety of immune mechanisms to discriminate between non-pathogenic and pathogenic invaders. It is able to maintain tolerance against the plethora of environmental antigens and to induce potent protective immunity to avoid mucosal colonisation and organism invasion by dangerous microbial pathogens. Mucosal immunisation with appropriate antigens and immunostimulatory molecules may induce potent protective immunity against harmful pathogens. Alternatively, mucosally-induced tolerance against auto-antigens or allergens may be generated by mucosal administration of these antigens alone or with immunomodulators potentiating regulatory responses. Here, we review the properties of the mucosal immune system and briefly discuss the advances in the development of mucosal vaccines for protection against infections and for the treatment of inflammatory disorders such as autoimmune diseases or type I allergies.     

PIMS modulates immune tolerance by negatively regulating Drosophila innate immune signaling

Metazoans tolerate commensal-gut microbiota by suppressing immune activation while maintaining the ability to launch rapid and balanced immune reactions to pathogenic bacteria. Little is known about the mechanisms underlying the establishment of this threshold. We report that a recently identified Drosophila immune regulator, which we call PGRP-LC-interacting inhibitor of Imd signaling (PIMS), is required to suppress the Imd innate immune signaling pathway in response to commensal bacteria. pims expression is Imd (immune deficiency) dependent, and its basal expression relies on the presence of commensal flora. In the absence of PIMS, resident bacteria trigger constitutive expression of antimicrobial peptide genes (AMPs). Moreover, pims mutants hyperactivate AMPs upon infection with Gram-negative bacteria. PIMS interacts with the peptidoglycan recognition protein (PGRP-LC), causing its depletion from the plasma membrane and shutdown of Imd signaling. Therefore, PIMS is required to establish immune tolerance to commensal bacteria and to maintain a balanced Imd response following exposure to bacterial infections.     

Innate immune mechanisms of colitis and colitis-associated colorectal cancer

The innate immune system provides first-line defences in response to invading microorganisms and endogenous danger signals by triggering robust inflammatory and antimicrobial responses. However, innate immune sensing of commensal microorganisms in the intestinal tract does not lead to chronic intestinal inflammation in healthy individuals, reflecting the intricacy of the regulatory mechanisms that tame the inflammatory response in the gut. Recent findings suggest that innate immune responses to commensal microorganisms, although once considered to be harmful, are necessary for intestinal homeostasis and immune tolerance. This Review discusses recent findings that identify a crucial role for innate immune effector molecules in protection against colitis and colitis-associated colorectal cancer and the therapeutic implications that ensue.     

cGAS-STING信号通路：免疫监视的重要机制

免疫系统识别病原微生物的主要机制之一是识别其核酸。环磷酸鸟苷-腺苷合成酶(cGAS)是一种胞质DNA感受器,感知病原DNA后激活cGAS-STING通路。该通路不仅介导天然免疫应答以抵抗多种含DNA的病原微生物感染,还能感知肿瘤来源的DNA而产生抗肿瘤免疫应答。然而,自体DNA对cGAS-STING通路的异常激活也会导致自身免疫性和炎症性疾病。本文综述了cGAS-STING信号通路及其在抗病毒天然免疫中的调控作用与功能,阐述了cGAS-STING通路在抗病毒感染和疾病中发挥的作用。     

Development of mucosal immunity in the first year of life and relationship to sudden infant death syndrome

The common mucosal immune system (CMIS) is an interconnecting network of immune structures that provides effective immunity to mucosal surfaces. The structures of the mucosal immune system are fully developed in utero by 28 weeks gestation, but in the absence of intrauterine infection, activation does not occur until after birth. Mucosal immune responses occur rapidly in the first weeks of life in response to extensive antigenic exposure. Maturation of the mucosal immune system and establishment of protective immunity varies between individuals but is usually fully developed in the first year of life, irrespective of gestational age at birth. In addition to exposure to pathogenic and commensal bacteria, the major modifier of the developmental patterns in the neonatal period is infant feeding practices. A period of heightened immune responses occurs during the maturation process, particularly between 1 and 6 months, which coincides with the age range during which most cases of sudden infant death syndrome (SIDS) occur. A hyper-immune mucosal response has been a common finding in infants whose death is classified as SIDS, particularly if in association with a prior upper respiratory infection. Inappropriate mucosal immune responses to an otherwise innocuous common antigen and the resulting inflammatory processes have been proposed as factors contributing to SIDS.     

Induction of cytokine formation by human intestinal bacteria in gut epithelial cell lines

Aims: To investigate the effects of human gut micro‐organisms on cytokine production by human intestinal cell lines. Methods and Results: Quantitative real‐time PCR assays were developed to measure the production of pro‐inflammatory (IL‐1α, IL‐6, IL‐18 and TNFα) and anti‐inflammatory (TGF‐β1, TGF‐β2, TGF‐β3, IL‐4 and IL‐10) cytokines in HT‐29 and Caco‐2 cell lines. They were co‐cultured with a range of mucosal bacteria isolated from ulcerative colitis patients, together with lactobacilli and bifidobacteria obtained from healthy people. HT‐29 cells were also co‐cultured with Campylobacter jejuni, enterotoxigenic Escherichia coli (ETEC), enteropathogenic E. coli and Salmonella typhimurium. The majority of commensal bacteria tested suppressed the expression of anti‐inflammatory cytokine mRNA, increased IL‐18, reduced IL‐1α, and with the exception of nonpathogenic E. coli, reduced TNF‐α. All overtly pathogenic species increased both pro‐inflammatory and anti‐inflammatory cytokine mRNA. Conclusion: Commensal and pathogenic species induced fundamentally different cytokine responses in human intestinal epithelial cell lines. Significance and Impact of the Study: Interactions between commensal bacteria tested in this study and the innate immune system were shown to be anti‐inflammatory in nature, in contrast to the pathogenic organisms investigated. These data contribute towards our understanding of how potential probiotic species can be used to suppress the pro‐inflammatory response in inflammatory bowel disease.     

The regulation of IgA class switching

IgA class switching is the process whereby B cells acquire the expression of IgA, the most abundant antibody isotype in mucosal secretions. IgA class switching occurs via both T-cell-dependent and T-cell-independent pathways, and the antibody targets both pathogenic and commensal microorganisms. This Review describes recent advances indicating that innate immune recognition of microbial signatures at the epithelial-cell barrier is central to the selective induction of mucosal IgA class switching. In addition, the mechanisms of IgA class switching at follicular and extrafollicular sites within the mucosal environment are summarized. A better understanding of these mechanisms may help in the development of more effective mucosal vaccines.     

Dendritic cells in the recognition of intestinal microbiota

Mucosal dendritic cells (DCs) constantly survey the luminal microenvironment which contains commensal microbiota and potentially harmful organisms regulating pathogen recognition and adaptive as well as innate defense activation. Distinct mechanisms are beginning to emerge by which intestinal antigen sampling and handling is achieved ensuring specificity and contributing to redundancy in pathogen detection. Distinct DC subsets are associated with these mechanisms and regulate specific innate or adaptive immune responses to help distinguish between commensal microbiota, pathogens and self antigens. Understanding DC biology in the mucosal immune system may contribute to the unraveling of infection routes of intestinal pathogens and may aid in developing novel vaccines and therapeutic strategies for the treatment of infectious and inflammatory diseases.     

MyD88 signalling plays a critical role in host defence by controlling pathogen burden and promoting epithelial cell homeostasis during Citrobacter rodentium-induced colitis

Myeloid differentiation factor (MyD)88, an adaptor protein shared by the Toll-interleukin 1 receptor superfamily, plays a critical role in host defence during many systemic bacterial infections by inducing protective inflammatory responses that limit bacterial growth. However, the role of innate responses during gastrointestinal (GI) infections is less clear, in part because the GI tract is tolerant to commensal antigens. The current study investigated the role of MyD88 following infection by the murine bacterial pathogen, Citrobacter rodentium . MyD88-deficient mice suffered a lethal colitis coincident with colonic mucosal ulcerations and bleeding. Their susceptibility was associated with an overwhelming bacterial burden and selectively impaired immune responses in colonic tissues, which included delayed inflammatory cell recruitment, reduced iNOS and abrogated production of TNF-α and IL-6 from MyD88-deficient macrophages and colons cultured ex vivo . Immunostaining for Ki67 and BrDU revealed that MyD88 signalling mediated epithelial hyper-proliferation in response to C. rodentium infection. Thus, MyD88-deficient mice could not promote epithelial cell turnover and repair, leading to deep bacterial invasion of colonic crypts, intestinal barrier dysfunction and, ultimately, widespread mucosal ulcerations. In conclusion, MyD88 signalling within the GI tract plays a critical role in mediating host defence against an enteric bacterial pathogen, by controlling bacterial numbers and promoting intestinal epithelial homeostasis.     

Cross-tolerization between Nod1 and Nod2 signaling results in reduced refractoriness to bacterial infection in Nod2-deficient macrophages

Nod2 is an intracellular innate immune receptor that plays a role in host defense and susceptibility to inflammatory disease. We show in this study that macrophages rendered refractory to TLR4 and Nod2 signaling by exposure to LPS and muramyl dipeptide (MDP) exhibit impaired TNF-alpha and IL-6 production in response to pathogenic Listeria monocytogenes and Yersinia pseudotuberculosis as well as commensal bacteria including Escherichia coli and Bacteroides fragilis. Surprisingly, Nod2 deficiency was associated with impaired tolerization in response to pathogenic and commensal bacteria. Mechanistically, reduced tolerization of Nod2-null macrophages was mediated by recognition of bacteria through Nod1 because it was abolished in macrophages deficient in Nod1 and Nod2. Consistently, Nod2-null macrophages tolerant to LPS and MDP showed enhanced production of TNF-alpha and IL-6 as well as increased NF-kappaB and MAPK activation in response to the dipeptide KF1B, the Nod1 agonist. Furthermore, reduced tolerization of Nod2-deficient macrophages in response to bacteria was abolished when mutant macrophages were also rendered tolerant to the Nod1 ligand. Finally, MDP stimulation induced refractoriness not only to MDP, but also to iE-DAP stimulation, providing a mechanism to explain the reduced tolerization of Nod2-deficient macrophages infected with bacteria. These results demonstrate that cross-tolerization between Nod1 and Nod2 leads to increase recognition of both pathogenic and commensal bacteria in Nod2-deficient macrophages pre-exposed to microbial ligands.     

The fifth dimension of innate immunity

Innate immunity has evolved as a first line defense against invading pathogens. Cellular and humoral elements of the innate immune system detect infectious parasites, initiate inflammatory resistance reactions and finally contribute to the elimination of the invaders. Repeated attacks by pathogenic agents induce adaptive responses of the innate immune system. Typically, reapplication of pathogens provokes tolerance of the affected organism. However, also stimulatory effects of primary infections on subsequent innate immune responses have been observed. The present overview touches an undervalued aspect in the innate immune response: Its pronounced dependency on pathogen load. In addition to localization and timing of innate immune responses the pathogen dose dependency might be considered as a “fifth dimension of innate immunity”. Experimental results and literature data are presented proposing a hormetic reaction pattern of innate immune cells depending on the dose of pathogens.     

Modulation of immune homeostasis by commensal bacteria

Intestinal bacteria form a resident community that has co-evolved with the mammalian host. In addition to playing important roles in digestion and harvesting energy, commensal bacteria are crucial for the proper functioning of mucosal immune defenses. Most of these functions have been attributed to the presence of large numbers of 'innocuous' resident bacteria that dilute or occupy niches for intestinal pathogens or induce innate immune responses that sequester bacteria in the lumen, thus quenching excessive activation of the mucosal immune system. However it has recently become obvious that commensal bacteria are not simply beneficial bystanders, but are important modulators of intestinal immune homeostasis and that the composition of the microbiota is a major factor in pre-determining the type and robustness of mucosal immune responses. Here we review specific examples of individual members of the microbiota that modify innate and adaptive immune responses, and we focus on potential mechanisms by which such species-specific signals are generated and transmitted to the host immune system.     

Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression

Flagellin, the structural component of bacterial flagella, is secreted by pathogenic and commensal bacteria. Flagellin activates proinflammatory gene expression in intestinal epithelia. However, only flagellin that contacts basolateral epithelial surfaces is proinflammatory; apical flagellin has no effect. Pathogenic Salmonella, but not commensal Escherichia coli, translocate flagellin across epithelia, thus activating epithelial proinflammatory gene expression. Investigating how epithelia detect flagellin revealed that cell surface expression of Toll-like receptor 5 (TLR5) conferred NF-kappaB gene expression in response to flagellin. The response depended on both extracellular leucine-rich repeats and intracellular Toll/IL-1R homology region of TLR5 as well as the adaptor protein MyD88. Furthermore, immunolocalization and cell surface-selective biotinylation revealed that TLR5 is expressed exclusively on the basolateral surface of intestinal epithelia, thus providing a molecular basis for the polarity of this innate immune response. Thus, detection of flagellin by basolateral TLR5 mediates epithelial-driven inflammatory responses to Salmonella.     

TLRs and chronic inflammation

After the discovery of Toll-like receptors (TLRs), innate immune mechanisms came back in the focus of scientific research. With more and more mechanisms of TLR biology known, it has become clear that these and also other innate immune receptors are not only of crucial importance in the immune response to invading pathogens, but also play a role in the homeostasis of commensal flora and in the response to stress and danger signals. In this respect, increasing evidence is found that inappropriate quantity or quality of TLR ligands or aberrant response to TLR activation plays a role in a variety of chronic inflammatory diseases. In this review, an overview of the currently known TLRs and their signaling pathways is given and reports about their expression and activation in chronic inflammatory diseases are recapitulated.     

Bacterial-mucosal interactions in inflammatory bowel disease: an alliance gone bad

The complex interaction of genetic, microbial, and environmental factors may result in continuous activation of the mucosal immune system leading to inflammatory bowel disease (IBD). Most present treatments for IBD involve altering or suppressing the aberrant immune response; however, the role of the intestinal microbiota in the pathophysiology of IBD is becoming more evident. The epithelial layer is essential for the proper functioning of the gastrointestinal tract, and its increased permeability to the luminal antigens may lead to the inflammatory processes and mucosal damage observed in IBD. Factors affecting the efficacy of the epithelial barrier include presence of pathogenic bacteria (e.g., Helicobacter spp.), presence of probiotic bacteria, availability of selected nutrients, and others. Defective function of the mucosal barrier might facilitate the contact of bacterial antigens and adjuvants with innate and adaptive immune cells to generate prolonged inflammatory responses. This review will briefly describe the complex structure of the epithelial barrier in the context of bacterial-mucosal interactions observed in human IBD and mouse models of colitis.     

Invariant natural killer T cells trigger adaptive lymphocytes to churn up bile

How innate immune response causes autoimmunity has remained an enigma. In this issue of Cell Host & Microbe, Mattner et al. demonstrate that invariant natural killer T cells activated by the mucosal commensal Novosphingobium aromaticivorans precipitate chronic T cell-mediated autoimmunity against small bile ducts that mirrors human primary biliary cirrhosis. These findings provide a mechanistic understanding of the role of innate immunity toward a microbe in the development of autoimmunity.     

Immunomodulatory mechanisms of lactobacilli

Over the past decade it has become clear that lactobacilli and other probiotic and commensal organisms can interact with mucosal immune cells or epithelial cells lining the mucosa to modulate specific functions of the mucosal immune system. The most well understood signalling mechanisms involve the innate pattern recognition receptors such as Toll-like receptors, nucleotide oligomerization domain-like receptors and C-type lectin receptors. Binding of microbe-associated molecular patterns with these receptors can activate antigen presenting cells and modulate their function through the expression of surface receptors, secreted cytokines and chemokines. In vitro the cytokine response of human peripheral blood mononuclear cells and dendritic cells to lactobacilli can be strikingly different depending on both the bacterial species and the strain. Several factors have been identified in lactobacilli that influence the immune response in vitro and in vivo including cell surface carbohydrates, enzymes modifying the structure of lipoteichoic acids and metabolites. In mice mechanistic studies point to a role for the homeostatic control of inducible T regulatory cells in the mucosal tissues as one possible immunomodulatory mechanism. Increasing evidence also suggests that induction of epithelial signalling by intestinal lactobacilli can modulate barrier functions, defensin production and regulate inflammatory signalling. Other probiotic mechanisms include modulation of the T cell effector subsets, enhancement of humoral immunity and interactions with the epithelial-associated dendritic cells and macrophages. A major challenge for the future will be to gain more knowledge about the interactions occurring between lactobacilli and the host in vivo and to understand the molecular basis of innate signalling in response to whole bacteria which trigger multiple signalling pathways.     

Pathogenic bacteria prime the induction of Toll-like receptor signalling in human colonic cells by the Gal/GalNAc lectin Carbohydrate Recognition Domain of Entamoeba histolytica

In mixed intestinal infections with Entamoeba histolytica trophozoites and enteropathogenic bacteria, which are wide-spread in areas of endemic amoebiasis, interaction between the pathogens could be an important factor in the occurrence of invasive disease. It has been reported that exposure of human colonic cells to enteropathogenic bacteria increased trophozoite adherence to the cells and their subsequent damage. We report here that the Carbohydrate Recognition Domain (CRD) of the amoebic Gal/GalNAc lectin binds to Toll-like receptors TLR-2 and TLR-4 in human colonic cells, activating the “classic” signalling pathway of these receptors. Activation induced expression of TLR-2 and TLR-4 mRNAs and the mRNAs of pro-inflammatory cytokines, as well as an increase in the corresponding proteins. Direct correlation was observed between the increased expression of TLRs and pro-inflammatory cytokines, the enhanced adhesion of trophozoites to the cells and the inflicted cell damage. When cells were exposed to pathogenic bacteria Staphylococcus aureus (Gram+) or Shigella dysenteriae (Gram−), elements of an innate immune response were induced. CRD by itself elicited a similar cell response, while exposure to a commensal Escherichia coli had a null effect. Pre-exposure of the cells to pathogenic bacteria and then to CRD rendered an inflammatory-like microenvironment that after addition of trophozoites facilitated greater cell destruction. Our results suggest that CRD is recognised by human colonic cells as a pathogen-associated-molecular-pattern-like molecule and as such can induce the expression of elements of an innate immune response. In the human host, an exacerbated inflammatory environment, derived from pathogen interplay, may be an important factor for development of invasive disease.