Mucosal surfaces such as the intestinal tract are continuously exposed to both potential pathogens and beneficial commensal microorganisms. This creates a requirement for a homeostatic balance ...between tolerance and immunity that represents a unique regulatory challenge to the mucosal immune system. Recent findings suggest that intestinal epithelial cells, although once considered a simple physical barrier, are a crucial cell lineage for maintaining intestinal immune homeostasis. This Review discusses recent findings that identify a cardinal role for epithelial cells in sampling the intestinal microenvironment, discriminating pathogenic and commensal microorganisms and influencing the function of antigen-presenting cells and lymphocytes.
Nearly half of the world's population harbors helminth infections or suffers from allergic disorders. A common feature of this population is the so-called "type 2 immune response," which confers ...protection against helminths, but also promotes pathologic responses associated with allergic inflammation. However, the mechanisms that initiate and control type 2 responses remain enigmatic. Recent advances have revealed a role for the innate immune system in orchestrating type 2 responses against a bewildering array of stimuli, from nanometer-sized allergens to 20-meter-long helminth parasites. Here, we review these advances and suggest that the human immune system has evolved multiple mechanisms of sensing such stimuli, from recognition of molecular patterns via innate immune receptors to detecting metabolic changes and tissue damage caused by these stimuli.
Interactions between immune and neuronal cells are pillars in tissue homeostasis
Maintenance of mammalian tissue homeostasis and function requires coordinated actions of multiple cellular and ...molecular networks. This complexity is reflected in the immune system, which is composed of a plethora of cells that constitute the innate and adaptive immune system and which can sense multiple endogenous and exogenous factors. Similarly, the nervous system includes a myriad of distinct neurons that perceive, integrate, and respond to ever-changing environmental conditions. Functional interactions between the neuronal and immune systems have been reported in health and disease, such as in multiple sclerosis, autism, cancer, and chronic inflammatory disorders (
1
). More recently, a number of studies have revealed that discrete neuronal and immune cells share anatomical localization and interact functionally, forming neuroimmune cell units (NICUs) that orchestrate tissue homeostasis and integrity (
2
). These findings are provoking a fundamental paradigm shift in our understanding of neuronal–immune cell interactions. A recent noteworthy example is the finding that the nervous system can have a major regulatory effect on multiple innate immune cells with functional impact in several physiological processes (
3
–
8
).
A previously unappreciated cell type of the innate immune system, termed innate lymphoid cells (ILCs), has been characterized in mice and humans and found to influence the induction, regulation and ...resolution of inflammation. ILCs have an important role in these processes in mouse models of infection, inflammation and tissue repair. Further, disease-association studies in defined patient populations have identified significant alterations in ILC responses, suggesting a potential role for these cell populations in human health and disease. In this review we discuss the emerging family of ILCs, the role of ILCs in inflammation, and how current or novel therapeutic strategies could be used to selectively modulate ILC responses and limit chronic inflammatory diseases.
The mammalian gastrointestinal tract, the site of digestion and nutrient absorption, harbors trillions of beneficial commensal microbes from all three domains of life. Commensal bacteria, in ...particular, are key participants in the digestion of food, and are responsible for the extraction and synthesis of nutrients and other metabolites that are essential for the maintenance of mammalian health. Many of these nutrients and metabolites derived from commensal bacteria have been implicated in the development, homeostasis and function of the immune system, suggesting that commensal bacteria may influence host immunity via nutrient- and metabolite-dependent mechanisms. Here we review the current knowledge of how commensal bacteria regulate the production and bioavailability of immunomodulatory, diet-dependent nutrients and metabolites and discuss how these commensal bacteria-derived products may regulate the development and function of the mammalian immune system.
Obesity is an increasingly prevalent disease worldwide. While genetic and environmental factors are known to regulate the development of obesity and associated metabolic diseases, emerging studies ...indicate that innate and adaptive immune cell responses in adipose tissue have critical roles in the regulation of metabolic homeostasis. In the lean state, type 2 cytokine-associated immune cell responses predominate in white adipose tissue and protect against weight gain and insulin resistance through direct effects on adipocytes and elicitation of beige adipose. In obesity, these metabolically beneficial immune pathways become dysregulated, and adipocytes and other factors initiate metabolically deleterious type 1 inflammation that impairs glucose metabolism. This review discusses our current understanding of the functions of different types of adipose tissue and how immune cells regulate adipocyte function and metabolic homeostasis in the context of health and disease. We also highlight the potential of targeting immuno-metabolic pathways as a therapeutic strategy to treat obesity and associated diseases.
This review provides a thorough discussion of our current understanding of how immune cells regulate adipocyte function and metabolic homeostasis in the context of health and disease, highlighting the potential of targeting immuno-metabolic pathways as a therapeutic strategy to treat obesity and associated diseases.
Research over the last 7 years has led to the formal identification of innate lymphoid cells (ILCs), increased the understanding of their tissue distribution and has established essential functions ...of ILCs in diverse physiological processes. These include resistance to pathogens, the regulation of autoimmune inflammation, tissue remodeling, cancer and metabolic homeostasis. Notably, many ILC functions appear to be regulated by mechanisms distinct from those of other innate and adaptive immune cells. In this Review, we focus on how group 2 ILC (ILC2) and group 3 ILC (ILC3) responses are regulated and how these cells interact with other immune and non-immune cells to mediate their functions. We highlight experimental evidence from mouse models and patient-based studies that have elucidated the effects of ILCs on the maintenance of tissue homeostasis and the consequences for health and disease.
The human intestine is colonized by an estimated 100 trillion bacteria. Some of these bacteria are essential for normal physiology, whereas others have been implicated in the pathogenesis of multiple ...inflammatory diseases including IBD and asthma. This review examines the influence of signals from intestinal bacteria on the homeostasis of the mammalian immune system in the context of health and disease. We review the bacterial composition of the mammalian intestine, known bacterial-derived immunoregulatory molecules, and the mammalian innate immune receptors that recognize them. We discuss the influence of bacterial-derived signals on immune cell function and the mechanisms by which these signals modulate the development and progression of inflammatory disease. We conclude with an examination of successes and future challenges in using bacterial communities or their products in the prevention or treatment of human disease.
The immune system and the peripheral nervous system are distributed throughout the body and surveil vital organs utilizing various sensory mechanisms. Previous studies have demonstrated that ...tissue-resident innate lymphoid cells (ILCs) and neurons are heavily enriched in the body’s barrier surfaces, where it is critical to detect and rapidly adapt to the changes in dietary, microbial and other environmental stimuli. However, our understanding of how these two sensory systems cooperatively integrate these diverse signals to orchestrate host responses remains incomplete. Recent research has provided insights into how neurotrophic and neuronally derived factors regulate the functions of ILCs, establishing the neuro–ILC axis as a crucial component of broader neuro–immune interactions. Further, neurons express receptors for many cytokines produced by ILCs, opening the possibility for bidirectional neuro–immune interactions in regulating tissue homeostasis and inflammation. This review highlights recent advances in the cellular and molecular mechanisms of neuro–ILC interactions and their potential therapeutic implications.
•Innate lymphoid cells (ILCs) colocalize with tissue-innervating peripheral neurons.•Neurotransmitters and neuropeptides directly regulate ILC responses.•Neuronal responses can be regulated by inflammatory cytokines.•Neuro–ILC interactions are potential therapeutic targets in inflammatory diseases.
The multifaceted organization of the immune system involves not only patrolling lymphocytes that constantly monitor antigen-presenting cells in secondary lymphoid organs but also immune cells that ...establish permanent tissue-residency. The integration in the respective tissue and the adaption to the organ milieu enable tissue-resident cells to establish signaling circuits with parenchymal cells to coordinate immune responses and maintain tissue homeostasis. Innate lymphoid cells (ILCs) are tissue-resident innate immune cells that have a similar functional diversity to T cells including lineage-specifying transcription factors that drive certain effector programs. Since their formal discovery 10 years ago, it has become clear that ILCs are present in almost every tissue but strongly enriched at barrier surfaces, where they regulate immunity to infection, chronic inflammation, and tissue maintenance. In this context, recent research has identified ILCs as key in orchestrating tissue homeostasis through their ability to sustain bidirectional interactions with epithelial cells, neurons, stromal cells, adipocytes, and many other tissue-resident cells. In this review, we provide a comprehensive discussion of recent studies that define the development and heterogeneity of ILC populations and their impact on innate and adaptive immunity. Further, we discuss emerging research on the influence of the nervous system, circadian rhythm, and developmental plasticity on ILC function. Uncovering the signaling circuits that control development and function of ILCs will provide an integrated view on how immune responses in tissues are synchronized with functional relevance far beyond the classical view of the role of the immune system in discrimination between self/non-self and host defense.
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