Visualizing cellular interactions with a generalized proximity reporter

Interactions among neighboring cells underpin many physiological processes ranging from early development to immune responses. When these interactions do not function properly, numerous pathologies, including infection and cancer, can result. Molecular imaging technologies, especially optical imaging, are uniquely suited to illuminate complex cellular interactions within the context of living tissues in the body. However, no tools yet exist that allow the detection of microscopic events, such as two cells coming into close proximity, on a global, whole-animal scale. We report here a broadly applicable, longitudinal strategy for probing interactions among cells in living subjects. This approach relies on the generation of bioluminescent light when two distinct cell populations come into close proximity, with the intensity of the optical signal correlating with relative cellular location. We demonstrate the ability of this reporter strategy to gauge cell–cell proximity in culture models in vitro and then evaluate this approach for imaging tumor–immune cell interactions using a murine breast cancer model. In these studies, our imaging strategy enabled the facile visualization of features that are otherwise difficult to observe with conventional imaging techniques, including detection of micrometastatic lesions and potential sites of tumor immunosurveillance. This proximity reporter will facilitate probing of numerous types of cell–cell interactions and will stimulate the development of similar techniques to detect rare events and pathological processes in live animals.     

Mucosal Immunity and the Onset of Allergic Disease

Mucosal barriers encounter an environment that is rich in pathogens that possess mechanisms for invading mucosal tissues. These barriers also encounter innocuous antigens, such as foods, airborne antigens, and microbiota. The mucosa has developed a sophisticated immune system that can mount robust immune responses against pathogenic antigens, while maintaining mucosal tolerance against non-pathogenic antigens. Accumulating evidence indicates that the mucosal epithelium, dendritic cells, and a subtype of T cells with regulatory properties play important roles in the development and maintenance of mucosal tolerance. Moreover, the micribiota also contribute to regulating the mucosal immune system. A failure to develop or the breakdown of mucosal tolerance can result in allergic diseases, such as food allergy and asthma. By taking advantage of the unique characteristics of the mucosal immune system, strategies that induce regulatory cells in vivo and, thereby, reconstitute mucosal tolerance may be used to develop novel therapies that are suitable for treating or preventing of allergic diseases.     

Targeting human mast cells expressing g-protein-coupled receptors in allergic diseases

The G-protein-coupled receptors (GPCRs) are the largest known group of integral membrane receptor proteins and are the most common targets of pharmacotherapy. Mast cells (MCs) have been reported to play an important role in allergic diseases, such as urticaria and bronchial asthma. There is an increasing body of clinical evidence that MCs are recruited into allergic reactions by non-IgE-dependent mechanisms. Human MCs are activated and secrete histamine in response to neuropeptides, such as substance P and somatostatin, mediated by a GPCR, MRGX2. The microenvironment surrounding MCs in their resident tissues is likely to contain multiple factors that modify antigen-dependent MC activation. MCs express various GPCRs, and since the function of human MCs is modulated by various GPCR ligands, such as adenosine and sphingosine-1-phosphate, which are present in high levels in the bronchial alveolar lavage fluid of asthmatic patients, the GPCRs expressed on MCs may play an important role in human allergic diseases. The GPCRs expressed on MCs may serve as drug targets for the treatment of allergic diseases.     

胃肠道肥大细胞与肠神经系统的相互作用

作为胃肠道免疫系统重要成员的肥大细胞与肠神经系统(ENS)间存在复杂的相互作用,其对胃肠道正常功能的维持至关重要,并与一些疾病的发生密切相关。本文综述了肥大细胞与ENS相互作用的解剖学基础和分子生物学机制及其在胃肠道疾病病理生理学机制中的作用,为探讨相关疾病新的治疗靶点提供了线索。     

The role of mast cells in allergic inflammation

The histochemical characteristics of human basophils and tissue mast cells were described over a century ago by Paul Ehrlich. When mast cells are activated by an allergen that binds to serum IgE attached to their Fc?RI receptors, they release cytokines, eicosanoids and their secretory granules. Mast cells are now thought to exert critical proinflammatory functions, as well as potential immunoregulatory roles, in various immune disorders through the release of mediators such as histamine, leukotrienes, cytokines chemokines, and neutral proteases (chymase and tryptase). The aim of this review is to describe the role of mast cells in allergic inflammation. Mast cells interact directly with bacteria and appear to play a vital role in host defense against pathogens. Drugs, such as glucocorticoids, cyclosporine and cromolyn have been shown to have inhibitory effects on mast cell degranulation and mediator release. This review shows that mast cells play an active role in such diverse diseases as asthma, rhinitis, middle ear infection, and pulmonary fibrosis. In conclusion, mast cells may not only contribute to the chronic airway inflammatory response, remodeling and symptomatology, but they may also have a central role in the initiation of the allergic immune response, that is providing signals inducing IgE synthesis by B-lymphocytes and inducing Th2 lymphocyte differentiation.     

Emerging role of mast cells and macrophages in cardiovascular and metabolic diseases

Mast cells are essential in allergic immune responses. Recent discoveries have revealed their direct participation in cardiovascular diseases and metabolic disorders. Although more sophisticated mechanisms are still unknown, data from animal studies suggest that mast cells act similarly to macrophages and other inflammatory cells and contribute to human diseases through cell-cell interactions and the release of proinflammatory cytokines, chemokines, and proteases to induce inflammatory cell recruitment, cell apoptosis, angiogenesis, and matrix protein remodeling. Reduced cardiovascular complications and improved metabolic symptoms in animals receiving over-the-counter antiallergy medications that stabilize mast cells open another era of mast cell biology and bring new hope to human patients suffering from these conditions.     

吲哚胺-2,3-双加氧酶及其在肿瘤方面免疫调节的研究进展

吲哚胺-2,3-双加氧酶是催化色氨酸沿犬尿氨酸分解代谢的限速酶,在哺乳动物组织和细胞中广泛表达.色氨酸耗竭及其代谢产物是调节免疫抑制和免疫耐受的重要机制,在多种生理和病理状态中发挥重要的作用.因此,吲哚胺-2,3-双加氧酶在器官移植、自身免疫性疾病和肿瘤等方面的治疗也成了研究的热点.     

Estrogen and estrogen receptor signaling promotes allergic immune responses: Effects on immune cells,cytokines, and inflammatory factors involved in allergy

Hypersensitivity occurs when the body is stimulated by an antigen, resulting in an immune response, and leads to a physiological disorder or abnormal tissue trauma. Various immune cells, cytokines, and inflammatory mediators are involved in the immune responses related to allergic diseases, which are the core of anaphylaxis. Estrogen receptors are widely distributed in immune cells, which combine with estrogen and participate in allergic responses by affecting immune cells, cytokines, and inflammatory factors. We aimed to summarize the association between estrogen and allergic reactions to provide a scientific basis for understanding and studying the mechanisms of allergic diseases.     

Pancreatic pain

Abdominal pain is an important clinical symptom in pancreatic diseases. There is increasing evidence that pain in chronic pancreatitis and pancreatic cancer is triggered by pancreatic neuropathy. Damage to intrapancreatic nerves seems to support the maintenance and exacerbation of neuropathic pain. In chronic pancreatitis, intrapancreatic nerves are invaded by immune cells. This observation led to the hypothesis that neuro-immune interactions play a role in the pathogenesis of chronic pancreatitis and the accompanying abdominal pain syndrome. Similarly, pancreatic cancer cells infiltrate the perineurium of local nerves, which may in part explain the severe pain experienced by the patients. Furthermore, perineural invasion extending into extrapancreatic nerves may preclude curative resection and thus often leads to local recurrence. In recent years, the involvement of a variety of neurotrophins and neuropeptides in the pathogenesis of pancreatic pain was discovered. This review summarises recent data on the mechanisms of neuropathy and pain generation in pancreatic disorders.     

Mast cell modulation of the immune response

Mast cells are present in nearly all vascularized tissues, but not the blood. They are best known for the prominent role they play in atopic disease. However, our current understanding of their direct and indirect roles in the immune response offers a more nuanced picture of both villain and hero. Although they are implicated in many inflammatory disorders, they also defend us from bacterial pathogens, prevent dangerous overreactions by the immune system, and even protect us from snake venom. Perhaps there is more to these maligned cells than we thought.     

Neurotrophins and asthma

The neurotrophins are a family of peptides that promote survival, growth, and differentiation of neurons. Neurotrophins may also influence the function of nonneuronal cell types, including immune cells. The development and maintenance of asthma is thought to involve the nervous system and the immune system, but the role that neurotrophins play in asthma is unknown. The cellular sources of the neurotrophins include mast cells, lymphocytes, macrophages, epithelial cells, smooth muscle cells, and eosinophils. The activation of neurotrophin receptors in immune cells and neurons involves ligand-induced homodimerization, which leads to activation of intrinsic Trk receptor kinase. The exact consequences of activating these receptors on immune cells is unknown, but rather than having unique actions on immune cells, the neurotrophins appear to act in concert with known immune regulating factors to modulate the maturation, accumulation, proliferation, and activation of immune cells. Neurotrophins can modulate afferent nerve function by stimulating the production of neuropeptides within airway afferent neurons. These neuropeptides may be released from the central terminals of airway afferent neurons, which leads to heightened autonomic reflex activity, and increased reactivity in the airways.     

Neuro-allergology: Mast cell–nerve cross-talk

Mast cells (MCs) are derived from hematopoietic stem cells in the bone marrow, and their maturation is regulated by the tissue environment, such as the skin, lung and gut, leading to host defense. Peripheral nerve fibers located in various tissues are involved in diverse physiological and pathological processes. Anatomical relationships between MCs and nerve fibers were reported to have been observed in various organs. Moreover, MCs are positive for a large number of receptors for classical neurotransmitters (e.g., acetylcholine and corticotropin-releasing hormone) and neuropeptides (e.g., substance P, calcitonin gene-related peptides and hemokinin), and MC's functions are regulated by those nerve-derived factors. Also, histamine and proteases produced and released by MCs modulate nerve fiber functions. This functional cross-talk between MCs and nerve fibers can play physiological and pathological roles. MCs are key effector cells of allergic inflammation, such as atopic dermatitis, airway inflammation and food allergy. Here, we summarize and discuss the molecular mechanisms underlying the functional and anatomical cross-talk between MCs and nerve fibers in allergic inflamed tissues.     

Mast cells in allergy and host defense.

Mast cells have been implicated in the pathogenesis of allergic diseases and in inflammatory responses associated with pathological immune and disease-related processes including fibrosis, autoimmune pathology, and neoplasia. Recent findings in animal models of bacterial infection also suggest that mast cells may have a protective role in host defense against pathogens in innate immunity along with the probable role of mast cells in acquired immunity against parasitic infections. Mast cells are strategically located at the host-environment interface and may provide an early defense against an invading pathogen. Mast cells express an array of adhesion and immune receptors that may assist in the recognition of invading pathogens. When activated, these cells then synthesize and release key immunoregulatory cytokines, one consequence of which is to mobilize a rapid and vigorous inflammatory response. However, although it has been demonstrated that mast cells may have a role in innate immunity in defined in vitro and animal models, it remains to be determined whether mast cells are protective in innate immune responses in humans.     

Angiopoietin/Tie2系统在血管新生与成熟过程中的表达及意义

血管的新生和成熟需要经过血管内皮细胞与血管周围细胞间相互作用等一系列复杂的生物学过程,这一过程受到多种细胞因子的调控。促血管生成素(angiopoietin,Ang)是近年发现的一个与血管新生与成熟密切相关的家族,包括4个成员,即Ang1、Ang2、Ang3和Ang4,其共同的特异性受体为Tie2。Ang及受体Tie2在生理性血管形成过程中对新生血管的形成、重构及成熟发挥重要的调控作用。另有研究显示,Ang/Tie2系统也参与了缺血后再灌、肿瘤及视网膜病变等多种病理性血管的形成过程。研究Ang/Tie2系统的生物学效应以及其在血管新生与成熟过程中的表达及意义,有助于深入了解相关疾病的发病机制并为疾病的治疗提供新线索。     

Mast Cell Interactions and Crosstalk in Regulating Allergic Inflammation

Purpose of Review

This review summarizes recent findings on mast cell biology with a focus on IgE-independent roles of mast cells in regulating allergic responses.

Recent Findings

Recent studies have described novel mast cell-derived molecules, both secreted and membrane-bound, that facilitate cross-talk with a variety of immune effector cells to mediate type 2 inflammatory responses.

Summary

Mast cells are complex and dynamic cells that are persistent in allergy and are capable of providing signals that lead to the initiation and persistence of allergic mechanisms.

     

Requirement of Gab2 for mast cell development and KitL/c-Kit signaling

Mast cells are thought to participate in a variety of immune responses, such as parasite resistance and the allergic reaction. Mast cell development depends on stem cell factor (Kit ligand) and its receptor, c-Kit. Gab2 is an adaptor molecule containing a pleckstrin homology domain and potential binding sites for SH2 and SH3 domains. Gab2 is phosphorylated on tyrosine after stimulation with cytokines and growth factors, including KitL. Gab2-deficient mice were created to define the physiological requirement for Gab2 in KitL/c-Kit signaling and mast cell development. In Gab2-deficient mice, the number of mast cells was reduced markedly in the stomach and less severely in the skin. Bone marrow-derived mast cells (BMMCs) from the Gab2-deficient mice grew poorly in response to KitL. KitL-induced ERK MAP kinase and Akt activation were impaired in Gab2-deficient BMMCs. These data indicate that Gab2 is required for mast cell development and KitL/c-Kit signaling.     

Mast cells synthesize, store, and release nerve growth factor.

Mast cells and nerve growth factor (NGF) have both been reported to be involved in neuroimmune interactions and tissue inflammation. In many peripheral tissues, mast cells interact with the innervating fibers. Changes in the behaviors of both of these elements occur after tissue injury/inflammation. As such conditions are typically associated with rapid mast cell activation and NGF accumulation in inflammatory exudates, we hypothesized that mast cells may be capable of producing NGF. Here we report that (i) NGF mRNA is expressed in adult rat peritoneal mast cells; (ii) anti-NGF antibodies clearly stain vesicular compartments of purified mast cells and mast cells in histological sections of adult rodent mesenchymal tissues; and (iii) medium conditioned by peritoneal mast cells contains biologically active NGF. Mast cells thus represent a newly recognized source of NGF. The known actions of NGF on peripheral nerve fibers and immune cells suggest that mast cell-derived NGF may control adaptive/reactive responses of the nervous and immune systems toward noxious tissue perturbations. Conversely, alterations in normal mast cell behaviors may provoke maladaptive neuroimmune tissue responses whose consequences could have profound implications in inflammatory disease states, including those of an autoimmune nature.     

Role of intracellular zinc in molecular and cellular function in allergic inflammatory diseases

Zinc is an essential micronutrient in human body and a vital cofactor for the function of numerous proteins encoded by the human genome. Zinc has a critical role in maintaining many biochemical and physiological processes at the molecular, cellular, and multiple organ and systemic levels. The alteration of zinc homeostasis causes dysfunction of many organs and systems.In the immune system, zinc regulates the differentiation, proliferation and function of inflammatory cells, including T cells, eosinophils, and B cells, by modifying several signaling pathways such as NFκB signaling pathways and TCR signals. An adequate zinc level is essential for proper immune responses and decreased zinc levels were reported in many allergic inflammatory diseases, including atopic dermatitis, bronchial asthma, and chronic rhinosinusitis. Decreased zinc levels often enhance inflammatory activation. On the other hand, the inflammatory conditions alter the intracellular homeostasis of zinc, often decreasing zinc levels. These findings implied that there could be a vicious cycle between zinc deficiency and inflammatory conditions.In this review, we present recent evidence on the involvement of zinc in atopic dermatitis, bronchial asthma, and chronic rhinosinusitis, with insights into the involvement of zinc in the underlying molecular and cellular mechanisms related to these allergic inflammatory diseases.     

Mast cell modulation of the vascular and lymphatic endothelium

Mast cells (MCs) promote a wide range of localized and systemic inflammatory responses. Their involvement in immediate as well as chronic inflammatory reactions at both local and distal sites points to an extraordinarily powerful immunoregulatory capacity with spatial and temporal versatility. MCs are preferentially found in close proximity to both vascular and lymphatic vessels. On activation, they undergo a biphasic secretory response involving the rapid release of prestored vasoactive mediators followed by de novo synthesized products. Many actions of MCs are related to their capacity to regulate vascular flow and permeability and to the recruitment of various inflammatory cells from the vasculature into inflammatory sites. These mediators often work in an additive fashion and achieve their inflammatory effects locally by directly acting on the vascular and lymphatic endothelia, but they also can affect distal sites. Along these lines, the lymphatic and endothelial vasculatures of the host act as a conduit for the dissemination of MC signals during inflammation. The central role of the MC-endothelial cell axis to immune homeostasis is emphasized by the fact that some of the most effective current treatments for inflammatory disorders are directed at interfering with this interaction.     

Airway innate lymphoid cells in the induction and regulation of allergy

The recent discovery of innate lymphoid cells has revolutionized our understanding of the pathogenesis of immune diseases including allergy and asthma. Innate lymphoid cells (ILCs) are a heterogeneous collection of lymphocytes that lack antigen-specificity (non-T, non-B cells) and potently produce characteristic cytokines of T cell subsets (Th1, Th2, Th17). ILCs are divided into group 1 (ILC1s), group 2 (ILC2s), or group 3 (ILC3s). Similar to Th2 cells, ILC2s produce IL-4, IL-5, and IL-13, among others, and are present in increased numbers in samples from patients with many allergic disorders including asthma and chronic rhinosinusitis (CRS). Animal models have identified that ILC2s contribute to eosinophilic tissue infiltration, airway hyperresponsiveness, mucus production, as well as coordinate adaptive immune responses. Finally, recent studies support regulation of ILC2s by neuro-immune mechanisms as well as demonstrate a significant degree of plasticity between ILC subsets that may impact the immune responses in asthma and allergic airway diseases. Here, we review the current literature on ILC2s in human asthma and allergic airway diseases, as well as highlight some recent mechanistic insights into ILC2 function from in vitro studies and in vivo animal models.