Neutrophils are the most abundant immune cells in humans and serve as first responders to a myriad of host perturbations. Equipped with a plethora of antimicrobial molecules, neutrophils invade sites of inflammation to eradicate pathogens and clear debris. Traditionally, neutrophils were thought to cause collateral tissue damage before dying at the site. However, the presence of neutrophil infiltration into sterile injuries (in the absence of infections) suggests additional roles for these cells. Now, the view of neutrophils as indiscriminate killers seems to be changing as evolving evidence suggests that neutrophils actively orchestrate resolution of inflammation and contribute to tissue repair. Novel concepts include the idea that neutrophils are key to revascularization and subsequently reverse-transmigrate back to the vasculature, actively leaving sites of tissue damage to re-home to functional niches in the lung and bone marrow. This Review scrutinizes the role of neutrophils in tissue damage and repair, discussing recent findings and raising unresolved questions around this intriguing immune cell.
Moritz Peiseler, Paul Kubes
Over the last ten years, immunologists have recognized the central importance of an emerging group of innate lymphoid cells (ILCs) in health and disease. Characterization of these cells has provided a molecular definition of ILCs and their tissue-specific functions. Although the lineage-defining transcription factors, cytokine production, and nomenclature parallel those of T helper cells, ILCs do not require adaptive immune programming. Both environmental and host-derived signals shape the function of these evolutionarily ancient cells, which provide pathogen protection and promote tissue restoration. As such, ILCs function as a double-edged sword, balancing the inflammatory and reparative responses that arise during injury and disease. This Review highlights our recent understanding of tissue-resident ILCs and the signals that regulate their contribution to inflammation and tissue repair in health and disease.
Jim G. Castellanos, Randy S. Longman
Macrophages are tissue-resident or infiltrated immune cells critical for innate immunity, normal tissue development, homeostasis, and repair of damaged tissue. Macrophage function is a sum of their ontogeny, the local environment in which they reside, and the type of injuries or pathogen to which they are exposed. In this Review, we discuss the role of macrophages in the restoration of tissue function after injury, highlighting important questions about how they respond to and modify the local microenvironment to restore homeostasis.
Satoshi Watanabe, Michael Alexander, Alexander V. Misharin, G.R. Scott Budinger
Immune cell populations determine the balance between ongoing damage and repair following tissue injury. Cells responding to a tissue-damaged environment have significant bioenergetic and biosynthetic needs. In addition to supporting these needs, metabolic pathways govern the function of pro-repair immune cells, including regulatory T cells and tissue macrophages. In this Review, we explore how specific features of the tissue-damaged environment such as hypoxia, oxidative stress, and nutrient depletion serve as metabolic cues to promote or impair the reparative functions of immune cell populations. Hypoxia, mitochondrial DNA stress, and altered redox balance each contribute to mechanisms regulating the response to tissue damage. For example, hypoxia induces changes in regulatory T cell and macrophage metabolic profiles, including generation of 2-hydroxyglutarate, which inhibits demethylase reactions to modulate cell fate and function. Reactive oxygen species abundant in oxidative environments cause damage to mitochondrial DNA, initiating signaling pathways that likewise control pro-repair cell function. Nutrient depletion following tissue damage also affects pro-repair cell function through metabolic signaling pathways, specifically those sensitive to the redox state of the cell. The study of immunometabolism as an immediate sensor and regulator of the tissue-damaged environment provides opportunities to consider mechanisms that facilitate healthy repair of tissue injury.
Benjamin D. Singer, Navdeep S. Chandel
Allergen-specific immunotherapy has shown promise for the treatment of food allergy and is currently being evaluated in clinical trials. Although immunotherapy can induce desensitization, the mechanisms underlying this process are not completely understood. Recent advances in high-throughput technologies along with concomitant advances in data analytics have enabled monitoring of cells at the single-cell level and increased the research focus on upstream cellular factors involved in the efficacy of immunotherapy, particularly the role of T cells. As our appreciation of different T cell subsets and their plasticity increases, the initial simplistic view that restoring Th1/Th2 balance by decreasing Th2 or increasing Th1 responses can ameliorate food allergy is being enhanced by a more complex model involving other T cell subsets, particularly Tregs. In this Review, we focus on the current understanding of T cell functions in food allergy, tolerance, and immunotherapy.
Vanitha Sampath, Kari C. Nadeau
The epithelial cell–derived cytokines thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 are central regulators of type 2 immunity, which drives a broad array of allergic responses. Often characterized as “alarmins” that are released by the barrier epithelium in response to external insults, these epithelial cell–derived cytokines were initially thought to act only early in allergic inflammation. Indeed, TSLP can condition dendritic cells to initiate type 2 responses, and IL-33 may influence susceptibility to asthma through its role in establishing the immune environment in the perinatal lungs. However, TSLP, IL-33, and IL-25 all regulate a broad spectrum of innate immune cell populations and are particularly potent in eliciting and activating type 2 innate lymphoid cells (ILC2s) that may act throughout allergic inflammation. Recent data suggest that a TSLP/ILC axis may mediate steroid resistance in asthma. Recent identification of memory Th2 cell subsets that are characterized by high receptor expression for TSLP, IL-33, and IL-25 further supports a role for these cytokines in allergic exacerbations. There is therefore growing interest in developing biologics that target TSLP, IL-33, and IL-25. This Review provides an overview of TSLP, IL-33, and IL-25 and the development of blocking antibodies that target these epithelial cell–derived cytokines.
Florence Roan, Kazushige Obata-Ninomiya, Steven F. Ziegler
The rising prevalence of allergies represents an increasing socioeconomic burden. A detailed understanding of the immunological mechanisms that underlie the development of allergic disease, as well as the processes that drive immune tolerance to allergens, will be instrumental in designing therapeutic strategies to treat and prevent allergic disease. Improved characterization of individual patients through the use of specific biomarkers and improved definitions of disease endotypes are paving the way for the use of targeted therapeutic approaches for personalized treatment. Allergen-specific immunotherapy and biologic therapies that target key molecules driving the Th2 response are already used in the clinic, and a wave of novel drug candidates are under development. In-depth analysis of the cells and tissues of patients treated with such targeted interventions provides a wealth of information on the mechanisms that drive allergies and tolerance to allergens. Here, we aim to deliver an overview of the current state of specific inhibitors used in the treatment of allergy, with a particular focus on asthma and atopic dermatitis, and provide insights into the roles of these molecules in immunological mechanisms of allergic disease.
Willem van de Veen, Mübeccel Akdis
A rapidly developing paradigm for modern health care is a proactive and individualized response to patients’ symptoms, combining precision diagnosis and personalized treatment. Precision medicine is becoming an overarching medical discipline that will require a better understanding of biomarkers, phenotypes, endotypes, genotypes, regiotypes, and theratypes of diseases. The 100-year-old personalized allergen-specific management of allergic diseases has particularly contributed to early awareness in precision medicine. Polyomics, big data, and systems biology have demonstrated a profound complexity and dynamic variability in allergic disease between individuals, as well as between regions. Escalating health care costs together with questionable efficacy of the current management of allergic diseases facilitated the emergence of the endotype-driven approach. We describe here a precision medicine approach that stratifies patients based on disease mechanisms to optimize management of allergic diseases.
Ioana Agache, Cezmi A. Akdis
Gastrointestinal (GI) allergic disease is an umbrella term used to describe a variety of adverse, food antigen–driven, immune-mediated diseases. Although these diseases vary mechanistically, common elements include a breakdown of immunologic tolerance, a biased type 2 immune response, and an impaired mucosal barrier. These pathways are influenced by diverse factors such as diet, infections, exposure to antibiotics and chemicals, GI microbiome composition, and genetic and epigenetic elements. Early childhood has emerged as a critical period when these factors have a dramatic impact on shaping the immune system and therefore triggering or protecting against the onset of GI allergic diseases. In this Review, we will discuss the latest findings on the molecular and cellular mechanisms that govern GI allergic diseases and how these findings have set the stage for emerging preventative and treatment strategies.
Nurit P. Azouz, Marc E. Rothenberg
The neuronal and immune systems exhibit bidirectional interactions that play a critical role in tissue homeostasis, infection, and inflammation. Neuron-derived neuropeptides and neurotransmitters regulate immune cell functions, whereas inflammatory mediators produced by immune cells enhance neuronal activation. In recent years, accumulating evidence suggests that peripheral neurons and immune cells are colocalized and affect each other in local tissues. A variety of cytokines, inflammatory mediators, neuropeptides, and neurotransmitters appear to facilitate this crosstalk and positive-feedback loops between multiple types of immune cells and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems. In this Review, we discuss these recent findings regarding neuro-immune crosstalk that are uncovering molecular mechanisms that regulate inflammation. Finally, neuro-immune crosstalk has a key role in the pathophysiology of allergic diseases, and we present evidence indicating that neuro-immune interactions regulate asthma pathophysiology through both direct and indirect mechanisms.
Hiroki Kabata, David Artis
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