Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut

Secretory IgA (SIgA) serves as the first line of defense in protecting the intestinal epithelium from enteric toxins and pathogenic microorganisms. Through a process known as immune exclusion, SIgA promotes the clearance of antigens and pathogenic microorganisms from the intestinal lumen by blocking their access to epithelial receptors, entrapping them in mucus, and facilitating their removal by peristaltic and mucociliary activities. In addition, SIgA functions in mucosal immunity and intestinal homeostasis through mechanisms that have only recently been revealed. In just the past several years, SIgA has been identified as having the capacity to directly quench bacterial virulence factors, influence composition of the intestinal microbiota by Fab-dependent and Fab-independent mechanisms, promote retro-transport of antigens across the intestinal epithelium to dendritic cell subsets in gut-associated lymphoid tissue, and, finally, to downregulate proinflammatory responses normally associated with the uptake of highly pathogenic bacteria and potentially allergenic antigens. This review summarizes the intrinsic biological activities now associated with SIgA and their relationships with immunity and intestinal homeostasis.     

Neural immunoregulation: emerging roles for nerves in immune homeostasis and disease

In this review, James Downing and Jaleel Miyan outline emerging evidence for neural mechanisms that contribute to specific categories of host defence. Involvement of direct innervation in the adaptive control of immunological responses complements an established view of neuroendocrine-immune modulation. The challenge remains to understand the integrative and homeostatic functions of 'hardwiring' of peripheral immune effector sites, its bearing on disorder and potential for therapeutic modification.     

The physiological and pathophysiological roles of eosinophils in the gastrointestinal tract

Eosinophils and the gastrointestinal tract interact in an intimate and enigmatic relationship. Under healthy conditions, the presence of eosinophils is limited almost exclusively to the digestive tract mucosa where they exert several effector and immunoregulatory functions. While their precise function in the gastrointestinal tract is not completely understood, it is likely that, together with different T cell subsets, eosinophils are involved in maintaining the immunologic homeostastis across the mucosal barrier under resting conditions. Eosinophils also play a role in several inflammatory conditions, such as intestinal infections, hypersensitivity reactions, primary eosinophilic inflammations and several other chronic intestinal disorders. Depending on the responsible trigger, their effects may be beneficial or detrimental. Here, we discuss the available information regarding the physiological and pathological functions of eosinophils within the gastrointestinal tract.     

The outsiders: emerging roles of ectonucleotidases in inflammation

Research on the biological roles of ectonucleoidases has revealed that CD73, an ecto-5 nucleotidase, plays a special role in the extracellular conversion of adenosine monophosphate to adenosine-specifically, as a checkpoint that determines whether the extracellular environment is proinflammatory (characterized by adenosine 5′-triphosphate-mediated responses) or anti-inflammatory (adenosine-mediated responses). Inactivating or inhibiting CD73 attenuates the extracellular formation of adenosine, exacerbating the severity of various inflammatory diseases. In this issue of Science Translational Medicine, Fl?gel and colleagues showed that CD73 can be pharmacologically exploited to convert an inactive adenosine precursor to an active, anti-inflammatory adenosine analog. In addition to attenuating inflammation associated with collagen-induced arthritis in a mouse model, this prodrug approach was site-selective, because the metabolic conversion relies on CD73, which is up-regulated in the inflammatory locus (the joint).     

JAM-related proteins in mucosal homeostasis and inflammation

Mucosal surfaces are lined by epithelial cells that form a physical barrier protecting the body against external noxious substances and pathogens. At a molecular level, the mucosal barrier is regulated by tight junctions (TJs) that seal the paracellular space between adjacent epithelial cells. Transmembrane proteins within TJs include junctional adhesion molecules (JAMs) that belong to the cortical thymocyte marker for Xenopus family of proteins. JAM family encompasses three classical members (JAM-A, JAM-B, and JAM-C) and related molecules including JAM4, JAM-like protein, Coxsackie and adenovirus receptor (CAR), CAR-like membrane protein and endothelial cell-selective adhesion molecule. JAMs have multiple functions that include regulation of endothelial and epithelial paracellular permeability, leukocyte recruitment during inflammation, angiogenesis, cell migration, and proliferation. In this review, we summarize the current knowledge regarding the roles of the JAM family members in the regulation of mucosal homeostasis and leukocyte trafficking with a particular emphasis on barrier function and its perturbation during pathological inflammation.     

Persistence of mucosal mast cells and eosinophils in Shigella-infected children

Cells of the innate immune system and their mediators were studied at the single-cell level in the rectums of pediatric and adult patients with Shigella infection to better understand why children are at higher risk for severe infection. Adult patients had increased infiltration of mucosal mast cells (MMC) at the acute stage (3 to 5 days after the onset of diarrhea) and eosinophils in early convalescence (14 to 16 days after onset). Increased expression of stem cell factor and prostaglandin H synthase-1 (PGHS-1) was associated with increased tryptase-K(i)67-double-positive MMC in the acute stage and increased apoptosis of MMC, which led to a rapid decline in early convalescence. The eosinophils demonstrated increased expression of major basic protein (MBP), eotaxin, and CCR3, as well as increased necrotic death. The neutrophils showed enhanced alpha-defensin and lactoferrin expression in the acute phase. In contrast to adults, the pediatric patients demonstrated delayed accumulation of mast cells and eosinophils, while alpha-defensin expression persisted during convalescence. In contrast, neutrophil counts and lactoferrin expression were reduced in children compared to adults. The results suggest that children with shigellosis have a persistent activation of the innate immune response in the convalescent phase, indicating delayed elimination of Shigella antigens compared to adults.     

Evaluation of site-specific and seasonal variation in colonic mucosal eosinophils

Several systemic disorders and gastrointestinal diseases may be associated with increased colonic mucosal eosinophils, which may vary in number throughout the normal colon. Some investigators have proposed that colonic eosinophilia reflects allergen exposure, although this hypothesis has never been validated, and values quantifying the number of mucosal eosinophils that can be regarded as a normal finding are lacking. The aims of this study were to determine the number of intramucosal eosinophils normally present throughout the colon and evaluate the relationship between colonic eosinophilia and seasonal allergen exposure. Eosinophils in the crypt epithelium and lamina propria were evaluated in 198 mucosal biopsy specimens obtained from the ascending (n = 98) and descending (n = 100) colon of patients with normal colonoscopic examinations. The cases were stratified into 12 groups, reflecting the months during which the samples were obtained, and the mean number of mucosal eosinophils was determined for each group. Daily air pollen counts were recorded, and the mean determined for each month. Fifty-five percent of mucosal biopsy specimens from the ascending colon contained eosinophils in the crypt epithelium, compared with only 5% of biopsy specimens from the descending colon (P < .001). Lamina propria eosinophils were, on average, 3 times more numerous in the ascending compared with the descending colon (P < .001). Mucosal eosinophils were slightly more numerous in samples obtained in April and May, corresponding to periods of highest pollen counts, but this relationship was not significant (P > .05). We conclude that intramucosal eosinophils are commonly present in the proximal colon but show only mild fluctuations with ambient allergen exposure.     

Intestinal stromal cells in mucosal immunity and homeostasis

A growing body of evidence suggests that non-hematopoietic stromal cells of the intestine have multiple roles in immune responses and inflammation at this mucosal site. Despite this, many still consider gut stromal cells as passive structural entities, with past research focused heavily on their roles in fibrosis, tumor progression, and wound healing, rather than their contributions to immune function. In this review, we discuss our current knowledge of stromal cells in intestinal immunity, highlighting the many immunological axes in which stromal cells have a functional role. We also consider emerging data that broaden the potential scope of their contribution to immunity in the gut and argue that these so-called “non-immune” cells are reclassified in light of their diverse contributions to intestinal innate immunity and the maintenance of mucosal homeostasis.     

The emerging roles of the STING adaptor protein in immunity and diseases

DNA that gains access to the cytoplasm generally serves as a danger signal for the hosts. An emerging paradigm for responding to cytosolic DNAs centres on the endoplasmic reticulum‐resident protein stimulator of interferon genes (STING, also known as MITA, ERIS or MPYS), the hub adaptor of the recently identified DNA sensors. Dynamic regulations of STING action are critical for shaping innate immune responses against microbial infections, as well as for preventing autoimmune diseases. STING is also indispensable for the detection of immunogenic tumours. A deeper understanding of STING modulations could be instrumental for developing novel immunotherapeutic strategies against infectious, autoimmune and cancerous diseases. In this review, we summarize the latest advances on the role of STING in the DNA‐triggered immune reactions, and underscore the critical issues that remain to be resolved in future studies.     

Small intestinal resident eosinophils maintain gut homeostasis following microbial colonization

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Cytoplasmic lipid bodies in eosinophils: central roles in eicosanoid generation

BACKGROUND: Lipid bodies are lipid-rich cytoplasmic inclusions which form in diverse cell types, including eosinophils. Lipid body numbers increase in vivo in leukocytes participating in inflammatory processes. Our interest in lipid bodies relates to the roles that these structures play in arachidonate metabolism by eosinophils and other leukocytes involved in inflammation. METHODS: Specific agonists, platelet-activating factor (PAF), two cis-unsaturated fatty acids (arachidonic and oleic acids) and a diglyceride (1-oleyl-2-acetyl-glycerol (OAG)), were used to stimulate lipid body formation in human eosinophils. Lipid bodies were enumerated and eosinophils were stimulated with submaximal calcium ionophore to generate leukotriene C4 (LTC4), which was quantitated by immunoassay. RESULTS: Lipid body formation was rapidly inducible in eosinophils by specific intracellular signaling pathways. PAF, the two cis-unsaturated fatty acids and OAG each stimulated lipid body formation in eosinophils. Increased numbers of lipid bodies correlated quantitatively with the 'priming' response of eosinophils to form enhanced amounts of the 5-lipoxygenase-derived eicosanoid, LTC4. CONCLUSION: Lipid bodies in eosinophils function as intracellular domains that are both depots of esterified arachidonate and sites at which regulated enymatic events relevant to arachidonate metabolism can occur. In conjunction with our findings that key eicosanoid-forming enzzymes, including cyclooxygenase, 5- and 15-lipoxygenase and LTC4 synthase, are localized at lipid bodies in eosinophils, the finding that induction of lipid body formation correlated quantitatively with enhanced LTC4 production indicate that lipid bodies are structurally distinct, inducible, non-nuclear sites for enhanced synthesis of paracrine eicosanoid mediators of inflammation.     

Established and emerging roles for mitochondria in neutrophils

Neutrophils are the most abundant innate immune cells in human blood, emerging as important players in a variety of diseases. Mitochondria are bioenergetic, biosynthetic, and signaling organelles critical for cell fate and function. Mitochondria have been overlooked in neutrophil research owing to the conventional view that neutrophils contain few, if any, competent mitochondria and do not rely on these organelles for adenosine triphosphate production. A growing body of evidence suggests that mitochondria participate in neutrophil biology at many levels, ranging from neutrophil development to chemotaxis, effector function, and cell death. Moreover, mitochondria and mitochondrial components, such as mitochondrial deoxyribonucleic acid, can be released by neutrophils to eliminate infection and/or shape immune response, depending on the specific context. In this review, we provide an update on the functional role of mitochondria in neutrophils, highlight mitochondria as key players in modulating the neutrophil phenotype and function during infection and inflammation, and discuss the possibilities and challenges to exploit the unique aspects of mitochondria in neutrophils for disease treatment.     

Mast cells and eosinophils as regulators of functional homeostasis in the gastric mucosa

The numerous mast cells of the interstitial tissue of the gastric mucosa are the sites of histamine synthesis and storage. If this biogenic amine is liberated from these cells it transmits stimulation of gastric acid secretion to the epithelial cells. However, the effect of this released histamine is limited by the eosinophilic leukocytes, which find their way to the origin of histamine and decompose it. The functional level of these two kinds of cells is controlled by the neuroendocrine system.     

The emerging roles of IFIT3 in antiviral innate immunity and cellular biology

The interferon-inducible protein with tetrapeptide repeats 3 (IFIT3) is one of the most important members in both the IFIT family and interferon-stimulated genes family. IFIT3 has typical features of the IFIT family in terms of gene and protein structures, and is able to be activated through the classical PRRs-IFN-JAK/STAT pathway. A variety of viruses can induce the expression of IFIT3, which in turn inhibits the replication of viruses, with the underlying mechanism showing its crucial role in antiviral innate immunity. Emerging studies have also identified that IFIT3 is involved in cellular biology changes, including cell proliferation, apoptosis, differentiation, and cancer development. In this review, we summarize the characteristics of IFIT3 with respect to molecular structure and regulatory pathways, highlighting the role of IFIT3 in antiviral innate immunity, as well as its diverse biological roles. We also discuss the potential of IFIT3 as a biomarker in disease diagnosis and therapy.     

Role of secretory IgA, secretory component, and eosinophils in mucosal inflammation

Eosinophils and their products are important in the pathophysiology of allergic inflammation in mucosal tissues. Secretory component (SC) bound to IgA mediates transepithelial transport of IgA. As another biological activity of SC, we have reported that secretory IgA (sIgA) and SC preferentially activate human eosinophils. When eosinophils were stimulated with immobilized sIgA, degranulation and superoxide production were greater than when stimulated with serum IgA. In contrast, neutrophils responded similarly to sIgA and serum IgA. Superoxide production by eosinophils stimulated with cytokines was enhanced synergistically by immobilized SC, while SC showed no effect on neutrophil activation. Eosinophil superoxide production stimulated with sIgA was abolished by anti-CD18 mAb, suggesting that beta2 integrins might be crucial for this reaction. There are several reports that SC and sIgA may play important roles in regulating eosinophil functions in vivo in diseases associated with mucosal eosinophilia and in various allergic diseases. It is speculated that eosinophils in the mucosa are activated by SC or sIgA, and that subsequent degranulation and superoxide production are induced.     

Regulatory B cells in autoimmune diseases and mucosal immune homeostasis

B lymphocytes contribute to physiological immunity through organogenesis of secondary lymphoid organs, presentation of antigen to T cells, production of antibodies, and secretion of cytokines. Their role in several autoimmune diseases, mainly as producers of pathogenic antibodies, is also well known. However, certain subsets of B cells are emerging as the important regulatory cell populations in both mouse and human. The regulatory functions of B cells have been demonstrated in a variety of mouse models of autoimmune diseases including collagen-induced arthritis (CIA), experiment autoimmune encephalomyelitis (EAE), anterior chamber-associated immune deviation (ACAID), diabetes, contact hypersensitivity (CHS), and intestinal mucosal inflammation. Accumulating evidence from both mouse and human studies confirms the existence of regulatory B cells, and is beginning to define their mechanisms of action. In this article, we first review the history of B cells with regulatory function in autoimmune diseases, and summarize the current understanding about the characterizations of such B-cell subsets. We then discuss the possible regulatory mechanisms of B cells, and specifically define the role of regulatory B cells in immune homeostasis in the intestine.     

The role of TLRs,NLRs, and RLRs in mucosal innate immunity and homeostasis

The mucosal surfaces of the gastrointestinal tract are continually exposed to an enormous antigenic load of microbial and dietary origin, yet homeostasis is maintained. Pattern recognition molecules (PRMs) have a key role in maintaining the integrity of the epithelial barrier and in promoting maturation of the mucosal immune system. Commensal bacteria modulate the expression of a broad range of genes involved in maintaining epithelial integrity, inflammatory responses, and production of antimicrobial peptides. Mice deficient in PRMs can develop intestinal inflammation, which is dependent on the microbiota, and in humans, PRM polymorphisms are associated with exacerbated inflammatory bowel disease. Innate immune responses and epithelial barrier function are regulated by PRM-induced signaling at multiple levels, from the selective expression of receptors on mucosal cells or compartments to the expression of negative regulators. Here, we describe recent advances in our understanding of innate signaling pathways, particularly by Toll-like receptors and nucleotide-binding domain and leucine-rich repeat containing receptors at mucosal surfaces.     

The emerging roles of extracellular vesicles as intercellular messengers in liver physiology and pathology

Extracellular vesicles (EVs) are membrane-enclosed particles released from almost all cell types. EVs mediate intercellular communication by delivering their surface and luminal cargoes, including nucleic acids, proteins, and lipids, which reflect the pathophysiological conditions of their cellular origins. Hepatocytes and hepatic non-parenchymal cells utilize EVs to regulate a wide spectrum of biological events inside the liver and transfer them to distant organs through systemic circulation. The liver also receives EVs from multiple organs and integrates these extrahepatic signals that participate in pathophysiological processes. EVs have recently attracted growing attention for their crucial roles in maintaining and regulating hepatic homeostasis. This review summarizes the roles of EVs in intrahepatic and interorgan communications under different pathophysiological conditions of the liver, with a focus on chronic liver diseases including nonalcoholic steatohepatitis, alcoholic hepatitis, viral hepatitis, liver fibrosis, and hepatocellular carcinoma. This review also discusses recent progress for potential therapeutic applications of EVs by targeting or enhancing EV-mediated cellular communication for the treatment of liver diseases.     

Basophils: emerging roles in the pathogenesis of allergic disease

After approximately 130 years since their discovery as rare granulocytes that circulate in blood, basophils are just now gaining respect as significant contributors in the pathogenesis underlying allergic inflammation and disease. While long known for secreting preformed and newly synthesized mediators and for selectively infiltrating tissue during immunoglobulin E (IgE)-mediated inflammation, their role has largely been viewed as redundant to that of tissue mast cells in functioning as effector cells. This line of thought has persisted even though it has been known in humans for approximately 20 years that basophils additionally produce relatively large quantities of cytokines, e.g. interleukin-4 (IL-4)/IL-13, that are central for the manifestations of allergic disease. Studies using novel IL-4 reporter mice have significantly added to the in vivo importance of basophils as IL-4 producing cells, with recent findings indicating that these cells also function as antigen-presenting cells essential in initiating T-helper 2 responses. If confirmed and translated to humans, these provocative findings will give new meaning to the role basophils have in allergic disease, and in immunology overall.