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Key Points Although the type 2 cytokine response has many important host-protective functions, dysregulated, chronic or hyperreactive type 2 immunity can contribute to the development of disease. Type 2 cytokines are crucial to the pathogenesis of many allergic and fibrotic diseases, they suppress the development of protective type 1 immunity to a wide range of viral, bacterial and protozoan pathogens, and they can promote tumorigenesis and tumour cell growth. As dysregulated type 2 immune responses are major drivers of disease, the mechanisms that control the intensity, maintenance and resolution of type 2 immunity are probably important regulators of disease progression. Several endogenous regulatory mechanisms work collaboratively to prevent or to limit the pathological consequences of sustained type 2 immunity. Inflammatory monocytes and tissues macrophages have emerged as important regulators of established type 2 immune responses. Therapeutic strategies that disrupt the recruitment, the expansion or maintenance of crucial myeloid cell populations could emerge as novel therapeutic approaches for a variety of type 2-driven diseases. Interferon-γ- and interleukin-4 (IL-4)- and/or IL-13-activated macrophages antagonize type 2 inflammation and fibrosis by competing with activated myofibroblasts that require the metabolites l-arginine and l-proline for collagen synthesis. IL-4- and/or IL-13-primed macrophages expressing arginase 1 also inhibit IL-13-driven fibrosis by suppressing the proliferation and the expansion of the CD4 + T helper 2 (T H 2) cell population. The IL-13 decoy receptor (IL-13Rα2), the immunosuppressive cytokine IL-10 and type 1 cytokines collaboratively suppress the development of type 2 cytokine-driven disease and immunity. Therapeutic strategies targeting type 2 cytokine signalling pathways, eosinophil development and recruitment, epithelial cell-derived alarmins, prostaglandins and regulatory T (T Reg ) cell activity are at different stages of development for type 2-driven disease. The type 2 cytokine response provides important host-protective functions, but dysregulated type 2 immune responses can contribute to the development of disease. In this Review, the author describes the regulatory mechanisms that limit the pathological consequences of persistent type 2 immunity. Type 2 immune responses are defined by the cytokines interleukin-4 (IL-4), IL-5, IL-9 and IL-13, which can either be host protective or have pathogenic activity. Type 2 immunity promotes antihelminth immunity, suppresses type 1-driven autoimmune disease, neutralizes toxins, maintains metabolic homeostasis, and regulates wound repair and tissue regeneration pathways following infection or injury. Nevertheless, when type 2 responses are dysregulated, they can become important drivers of disease. Type 2 immunity induces a complex inflammatory response characterized by eosinophils, mast cells, basophils, type 2 innate lymphoid cells, IL-4-and/or IL-13-conditioned macrophages and T helper 2 (T H 2) cells, which are crucial to the pathogenesis of many allergic and fibrotic disorders. As chronic type 2 immune responses promote disease, the mechanisms that regulate their maintenance are thought to function as crucial disease modifiers. This Review discusses the many endogenous negative regulatory mechanisms that antagonize type 2 immunity and highlights how therapies that target some of these pathways are being developed to treat type 2-mediated disease.

Fibrosis can affect any organ and is responsible for up to 45% of all deaths in the industrialized world. It has long been thought to be relentlessly progressive and irreversible, but both preclinical models and clinical trials in various organ systems have shown that fibrosis is a highly dynamic process. This has clear implications for therapeutic interventions that are designed to capitalize on this inherent plasticity. However, despite substantial progress in our understanding of the pathobiology of fibrosis, a translational gap remains between the identification of putative antifibrotic targets and conversion of this knowledge into effective treatments in humans. Here we discuss the transformative experimental strategies that are being leveraged to dissect the key cellular and molecular mechanisms that regulate fibrosis, and the translational approaches that are enabling the emergence of precision medicine-based therapies for patients with fibrosis. This review discusses how single-cell profiling and other technological advances are increasing our understanding of the mechanisms of fibrosis, thereby accelerating the discovery, development and testing of new treatments.

Tissue repair after injury is a complex, metabolically demanding process. Depending on the tissue’s regenerative capacity and the quality of the inflammatory response, the outcome is generally imperfect, with some degree of fibrosis, which is defined by aberrant accumulation of collagenous connective tissue. Inflammatory cells multitask at the wound site by facilitating wound debridement and producing chemokines, metabolites, and growth factors. If this well-orchestrated response becomes dysregulated, the wound can become chronic or progressively fibrotic, with both outcomes impairing tissue function, which can ultimately lead to organ failure and death. Here we review the current understanding of the role of inflammation and cell metabolism in tissue-regenerative responses, highlight emerging concepts that may expand therapeutic perspectives, and briefly discuss where important knowledge gaps remain.

Fibrosis is a key aspect of many chronic inflammatory diseases and can affect almost every tissue in the body. This review discusses recent advances in our understanding of the mechanisms of fibrosis, focusing on the innate and adaptive immune responses. It also describes how some of these crucial pathogenic pathways are being therapeutically targeted in the clinic. Fibrosis is a key aspect of many chronic inflammatory diseases and can affect almost every tissue in the body. This review discusses recent advances in our understanding of the mechanisms of fibrosis, focusing on the innate and adaptive immune responses. It also describes how some of these crucial pathogenic pathways are being therapeutically targeted in the clinic. Fibrosis is a pathological feature of most chronic inflammatory diseases. Fibrosis, or scarring, is defined by the accumulation of excess extracellular matrix components. If highly progressive, the fibrotic process eventually leads to organ malfunction and death. Fibrosis affects nearly every tissue in the body. Here we discuss how key components of the innate and adaptive immune response contribute to the pathogenesis of fibrosis. We also describe how cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix–producing myofibroblasts. Finally, we highlight some of the key mechanisms and pathways of fibrosis that are being targeted as potential therapies for a variety of important human diseases.

Key Points Macrophages are highly heterogenous cells that can rapidly change their function in response to local microenvironmental signals. Although distinct macrophage subsets with unique functional abilities have been described, it is generally believed that macrophages represent a spectrum of activated phenotypes rather than discrete stable subpopulations. They adopt context-dependent phenotypes that either promote or inhibit host antimicrobial defence, antitumour immune responses and inflammatory responses. Macrophages ingest and kill pathogens and maintain healthy tissue by removing dead cells and debris. Because macrophages must be selective of the cells and materials they phagocytose, they use pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), C-type lectin receptors, scavenger receptors, retinoic acid-inducible gene 1 (RIG1)-like helicase receptors (RLRs) and NOD-like receptors, to recognize signals associated with invading pathogens, foreign substances (for example, silica or asbestos), and dead or dying cells. Various macrophage subsets with distinct immune functions have been described. Classically activated macrophages (M1 macrophages) mediate defence of the host from various bacteria, protozoa and viruses, and also mediate antitumour immune responses. Alternatively activated macrophages (M2 macrophages) have an anti-inflammatory function and regulate wound healing. 'Regulatory' macrophages can secrete large amounts of interleukin-10 (IL-10) in response to Fc receptor-γ ligation. Other, less-well-defined macrophage subsets include tumour-associated macrophages, which suppress antitumour immunity, and myeloid-derived suppressor cells. Alternatively activated macrophages regulate tissue repair and suppress tissue-destructive M1 responses. They express immunoregulatory proteins such as IL-10, resistin-like molecule-α (RELMα), chitinase-like proteins and arginase 1 (ARG1), which have been shown to decrease the magnitude and duration of inflammatory responses and promote wound healing. Inflammatory (M1) and suppressive (M2) macrophages are crucially involved in the initiation and resolution of immune responses. Thus, macrophages exhibit both protective and pathogenic roles in a wide range of autoimmune and inflammatory diseases. Although murine M1- and M2-polarized macrophage subsets are relatively easy to distinguish on the basis of combinatorial gene expression profiles, the identification of equivalent subsets in humans has been less clear. The regulation of macrophages in the tissues remains unclear. We also do not understand how homeostasis is restored after infection, how the response to damaged tissues is resolved and what mechanisms are involved in the layered hierarchy of macrophage activation in situ. Research is needed on mechanisms that regulate the plasticity and stability of macrophage populations in vivo . Identifying the transcription factors and epigenetic changes that control macrophage plasticity will advance the field. Macrophages exhibit remarkable plasticity and adopt pro- or anti-inflammatory phenotypes in response to environmental signals. This Review article by Murray and Wynn discusses the different macrophage subsets and their contribution to tissue homeostasis and disease pathogenesis. Macrophages are strategically located throughout the body tissues, where they ingest and process foreign materials, dead cells and debris and recruit additional macrophages in response to inflammatory signals. They are highly heterogeneous cells that can rapidly change their function in response to local microenvironmental signals. In this Review, we discuss the four stages of orderly inflammation mediated by macrophages: recruitment to tissues; differentiation and activation in situ ; conversion to suppressive cells; and restoration of tissue homeostasis. We also discuss the protective and pathogenic functions of the various macrophage subsets in antimicrobial defence, antitumour immune responses, metabolism and obesity, allergy and asthma, tumorigenesis, autoimmunity, atherosclerosis, fibrosis and wound healing. Finally, we briefly discuss the characterization of macrophage heterogeneity in humans.

The cardinal features of adaptive immunity are memory and antigen-specificity. Since Th2 cells are part of the adaptive immune system, this raises the question of why we need to \"remember\" to repair the wounds that are induced by specific parasites. [...]Th2 cytokines mediate rapid repair while also minimizing the number of incoming parasites via IgE or flushing out intestinal parasites via alterations to gut physiology and excess mucus production.