Summary: This review discusses recent advancements in understanding type 2 immune responses in allergic diseases of the skin and lungs, such as asthma and atopic dermatitis. It highlights epithelial-derived cytokines like IL-25, IL-33, and TSLP as crucial activators of type 2 responses, and identifies Th2 cells and innate lymphoid cells (ILCs) as producers of key cytokines including IL-4, IL-5, IL-9, and IL-13. The abstract details the specific functions of these cytokines in driving allergic inflammation, such as IL-4 and IL-13 in IgE production, immune cell migration, and barrier function, and IL-5 in eosinophil activation and survival. It also notes the contribution of Type 2 ILCs to asthma pathogenesis by enhancing Th2 cell and eosinophil activity, and mentions current therapeutic strategies targeting type 2 inflammation, while acknowledging the complexity and heterogeneity of patient responses.

Summary: This review discusses chronic inflammatory airway diseases like asthma, highlighting that their pathophysiology is driven by type 2 inflammation involving both innate lymphoid cells (ILC2s) and adaptive T-helper 2 (Th2) cells. Both cell types produce key type-2 cytokines such as IL-4, IL-5, and IL-13, which mediate various aspects of the inflammatory cascade, including IgE production, barrier disruption, tissue remodelling, and eosinophil trafficking, leading to characteristic symptoms. The abstract also touches upon asthma heterogeneity, the importance of biomarkers, and the development of targeted biological therapies based on this understanding of type 2 inflammation.

Summary: This review discusses how airway epithelial cells release alarmin cytokines (IL-25, IL-33, TSLP) upon exposure to stimuli like allergens, which then interact with receptors on various cells, including ILC2 cells, dendritic cells, and others. These alarmins are key drivers of type 2-high responses in asthma, and targeting them in mouse models has shown reduced disease chronicity. The review will explore the mechanisms of alarmin secretion, their receptor interactions modulating downstream allergic inflammation, and current therapeutic strategies targeting these mediators, noting their impact on eosinophilic asthma and clinical outcomes from trials like NAVIGATOR.

Summary: This study investigates how allergens induce T helper 2 (Th2) cell differentiation, a key process in allergic inflammation. The researchers demonstrate that group 2 innate lymphoid cells (ILC2s) are essential for mounting a robust Th2 response to the allergen papain, as evidenced by impaired allergic lung inflammation and elevated immunoglobulin E titers in ILC2-deficient mice. They found that ILC2-derived IL-13, not IL-4, is critical for promoting dendritic cell migration to lymph nodes, which in turn primes naive T cells into Th2 cells. The activation of ILC2s and subsequent Th2 cell differentiation by papain was dependent on IL-33, suggesting a common pathway for allergen-induced Th2 responses.

Summary: This paper reviews the role of Group 2 Innate Lymphoid Cells (ILC2s) in allergic asthma, highlighting their function in type 2 immunity, tissue homeostasis, and their contribution to allergy and asthma when inappropriately activated. The abstract states that ILC2s in the lungs rapidly respond to epithelium-derived alarmins (like IL-33, IL-25, TSLP) by producing type 2 effector cytokines such as IL-4, IL-5, and IL-13. It emphasizes their association with asthma severity and their function as 'playmakers' in experimental lung inflammation models, receiving signals from various cells and the nervous system to elicit type 2 immune effector functions and potentiate CD4+ T helper cell activation, which are characteristic of asthma pathology. Recent findings on microenvironmental cues regulating ILC2s and their plasticity are noted as improving the understanding of asthma immunoregulation and opening avenues for drug discovery.

Summary: This review discusses type 2 immune responses in allergic inflammation and asthma, distinguishing between atopic and non-atopic asthma where innate immune cells like ILC2s and eosinophils play a significant role. It highlights the IL-33/TSLP-basophil-ILC2-IL-5/IL-13 axis as a key innate network driving allergic responses, even in the absence of Th2 cells, and notes the contribution of these innate cells to adaptive Th2 responses in chronic phases, emphasizing the cross-talk between innate and adaptive immunity in lung inflammation.

Summary: This review discusses the increasing prevalence of allergic diseases such as asthma, atopic rhinitis, and atopic dermatitis, attributing them to type 2 immune responses initiated by innate immunity. It highlights the ILC2-DC-Th2 axis as a central pathway mediating type 2 inflammation, with ILC2s playing a strong role in these diseases. The abstract notes that ILC2s are activated by epithelial-derived cytokines like IL-25, IL-33, and TSLP, as well as mast cell mediators, and that their production of type 2 cytokines (IL-4, IL-5, IL-9, IL-13) makes them a significant therapeutic target.

Summary: This study investigates the role of eosinophil extracellular traps (EETs) in severe asthma (SA) pathogenesis by examining their interaction with type 2 innate lymphoid cells (ILC2s) and airway epithelium. Researchers found elevated EET+ eosinophils and ILC2s in patients with SA, with a positive correlation between them. In mouse models, EET injection led to increased epithelium-derived cytokines (including IL-33 and TSLP), eosinophil/neutrophil infiltration, and a higher proportion of IL-5/IL-13 producing ILC2s, ultimately causing airway hyperresponsiveness (AHR). These effects were suppressed by anti-IL-33 or anti-TSLP antibodies, suggesting that EETs enhance innate and type 2 immune responses in SA, potentially benefiting from epithelium-targeting biologics.

Summary: This study investigated the role of Group 2 Innate Lymphoid Cells (ILC2s) in allergen-induced airway eosinophilic responses in asthma patients. Using a crossover allergen challenge study in 10 subjects, researchers found significant increases in total, IL-5+, IL-13+, and CRTH2+ ILC2s within the sputum 24 hours after allergen challenge, while blood ILC2 levels decreased. CD4+ T lymphocytes also increased locally and systemically. Airway eosinophilia correlated with IL-5+ ILC2s, and both ILC2s and CD4+ T cells showed steroid sensitivity in vitro, suggesting a mechanism for steroid effectiveness in mild asthma.

Summary: This review focuses on the role of Group 2 Innate Lymphoid Cells (ILC2s) in house dust mite (HDM)-induced asthma mouse models, highlighting their crucial involvement in eosinophilic airway inflammation through the release of T helper 2 cytokines. It explains that HDMs, acting as both allergens and cysteine proteases, induce epithelial cells to produce alarmins like IL-25, IL-33, and TSLP, which in turn activate ILC2s. Activated ILC2s then produce cytokines such as IL-5, IL-9, IL-13, and amphiregulin, contributing to asthma pathogenesis, and the paper aims to guide researchers in understanding these molecular mechanisms.

Summary: This article reviews the therapeutic potential of targeting Group 2 Innate Lymphoid Cells (ILC2s) in asthma, highlighting their crucial role in the pathophysiology, including airway eosinophilic inflammation. It details how ILC2s are activated by epithelial-derived cytokines such as IL-25, IL-33, and TSLP, leading to the release of type 2 cytokines like IL-5 and IL-13, which drive airway inflammation and hyperreactivity. The review also touches upon ILC2 regulation by other immune cells, potential steroid resistance conferred by ILC2 activation, and the efficacy of current biologics targeting type 2 inflammation, suggesting a promising therapeutic avenue for asthma treatment.

Summary: This review discusses the significant role of group 2 innate lymphoid cells (ILC2) in the initiation and orchestration of respiratory allergic inflammation, which affects millions worldwide. ILC2s are identified as crucial mediators of inflammation and tissue remodeling, capable of secreting substantial amounts of signature cytokines rapidly to instruct both innate and adaptive immune responses. The paper aims to review recent literature on ILC2 function in allergic respiratory tract inflammation, explore therapeutic strategies targeting pulmonary allergic inflammation and their impact on ILC2s, and consider the potential use of human ILC2s for diagnostic purposes.

Summary: This review discusses Interleukin (IL)-33, an alarmin passively released from structural cells upon tissue damage, and its significant role in type-2 innate immunity. It details how IL-33 activates immune cells such as eosinophils, basophils, mast cells, macrophages, and group 2 innate lymphoid cells (ILC2s) via its receptor ST2, thereby regulating allergic inflammation in conditions like allergic asthma. The paper also explores therapeutic strategies targeting the IL-33/ST2 axis.

Summary: This review article highlights the significant role of Group 2 Innate Lymphoid Cells (ILC2s) in the pathogenesis of asthma, a chronic airway inflammatory disease. It notes that ILC2s, lacking antigen-specific receptors, are activated by epithelial-derived cytokines and contribute to airway eosinophilic inflammation independently of antigen. The abstract also points out potential involvement in steroid resistance and emphasizes that studies in both mice and humans demonstrate ILC2s' role in inducing airway inflammation through various mediators, including their collaboration with T helper type 2 (Th2) cells. Furthermore, it mentions increased ILC2 frequencies in asthma patients, suggesting their contribution to immune regulation in the disease.

Summary: This paper reviews the role of Group 2 Innate Lymphoid Cells (ILC2s) in allergic asthma, noting their production of Th2 cytokines like IL-5 and IL-13, and their involvement in inducing eosinophilia and airway hyper-reactivity (AHR) in mouse models, as well as their significance in human asthma persistence. The abstract highlights that induced regulatory T cells (iTregs) suppress ILC2-driven cytokine production through direct contact and the ICOS-ICOSL pathway, and are also influenced by IL-10 and TGF-β1, positioning iTregs as potential therapeutic targets for ILC2-mediated allergic asthma.

Summary: This study utilized a human experimental allergen challenge model with noninvasive nasal curettage to assess the role of mucosal type 2 innate lymphoid cells (ILC2s) in allergic rhinitis. Following allergen provocation, subjects with atopy showed increased upper airway symptoms, a greater presence of ILC2s, eosinophils, and neutrophils, and elevated levels of IL-5, prostaglandin D2, and chemokines for eosinophils and T-helper type 2 cells compared to healthy subjects. The recruitment of ILC2s was particularly pronounced in individuals with high IgE and airway eosinophilia, highlighting their significant contribution to the early allergic response to aeroallergens in the airways.

Summary: This study demonstrates that type 2 pulmonary innate lymphoid cells (ILC2s) are significant contributors to IL-5 and IL-13 production in experimental asthma models. Using intranasal administration of IL-25 or IL-33 to induce an asthma phenotype in mice, the researchers observed an accumulation of ILC2s in the lungs and bronchoalveolar lavage (BAL) fluid, where they constituted a substantial portion of IL-5 and IL-13 producing cells. Furthermore, in house dust mite- or ovalbumin-induced allergic asthma, ILC2s were identified as a major source of these key cytokines, with their contribution to IL-5 and IL-13 production in the lung being comparable to that of T helper 2 (Th2) cells, concluding that both cell types drive allergic airway inflammation.

Summary: This abstract highlights the emerging central role of type 2 innate lymphoid cells (ILC2s) in eosinophilic asthma, proposing they initiate inflammatory responses. It notes that ILC2s, which are non-T, non-B cells lacking antigen specificity, produce higher levels of IL-5 and IL-13 than CD4+ T cells in vitro. The abstract also points out that ILC2s are increased in the airways of severe asthmatics, particularly those with uncontrolled eosinophilia, and suggests that controlling ILC2 activation could be a therapeutic target for airway diseases.

Summary: This study investigates the phenotypic heterogeneity of Group 2 Innate Lymphoid Cells (ILC2s) in allergic airway inflammation, comparing IL-33- and house dust mite (HDM)-driven models. The researchers found that ILC2 surface marker expression is dynamic, varying with activation mode (T cell-dependent vs. independent), time, and tissue compartment, and that ILC2s can produce IL-5 and IL-13. While IL-33-activated ILC2s showed a uniform phenotype, HDM-activated ILC2s were heterogeneous but retained cytokine-producing capacity, and could revert to a CD25high phenotype upon IL-33 stimulation. Transcriptional profiling revealed distinct gene expression patterns, with HDM-stimulated ILC2s involved in adaptive immunity regulation and IL-33-stimulated ILC2s expressing proliferation and cytokine genes. ILC2s were observed in lung submucosa and infiltrates near T cells in chronic inflammation, highlighting their complex and dynamic role in the pathogenesis of allergic airway disease.

Summary: This review discusses Type 2 innate lymphoid cells (ILC2s) as a key player in allergic asthma, a Th2-mediated chronic inflammatory disease characterized by IL-4, IL-5, and IL-13. ILC2s, found in epithelial compartments in mice and humans, rapidly produce IL-5 and IL-13 in response to epithelial-derived cytokines, contributing to eosinophilic infiltration, mucus production, and airway hyperresponsiveness. The paper highlights findings from murine studies that elucidate fundamental mechanisms of ILC2 function in initiating and maintaining adaptive type 2 immune responses in asthma immunopathology.

Summary: This review examines the mechanisms governing the recruitment of eosinophils and group 2 innate lymphoid cells (ILC2s) to the airways in asthma, a disease characterized by Type 2 cytokines and eosinophil infiltration. It highlights the significant contribution of ILC2s to producing IL-5 and IL-13, which amplify eosinophil recruitment, and discusses how therapies targeting these cytokines improve asthma symptoms and reduce eosinophil counts. The paper emphasizes the roles of chemokines like eotaxins and other chemoattractants, including bioactive lipids, in this process, and notes differences in eosinophil biology between human and mouse models.

Summary: This review discusses Interleukin (IL)-33, a key cytokine in type 2 immunity and allergic airway diseases, highlighting its expression in lung epithelial cells and its critical roles in both innate and adaptive immune responses. It emphasizes the essential axis formed by IL-33 and group 2 innate lymphoid cells (ILC2s) for rapid immune responses and tissue homeostasis, and details IL-33's interactions with dendritic cells, Th2 cells, and other immune cells in influencing chronic airway inflammation and tissue remodeling. The abstract notes that elevated IL-33 and ILC2 levels in patients with allergic airway diseases suggest IL-33's significant role in disease pathogenesis and potential utility as biomarkers.

Summary: This review discusses the increasing interest in type 2 immune responses driven by epithelium-derived cytokines such as IL-33, IL-25, and TSLP, highlighting Group 2 Innate Lymphoid Cells (ILC2s) as effector immune cells capable of secreting proallergic cytokines like IL-5 and IL-13. The paper aims to study the role of ILC2s in various allergic disorders, including asthma, allergic rhinitis, atopic dermatitis, and food allergies, based on a MEDLINE literature search. The findings indicate an important role for ILC2s in these conditions, suggesting they may represent a new therapeutic target, and the review covers current understanding of ILC2 biology, function, and regulation in allergic diseases.

Summary: This review focuses on the regulation of Group 2 Innate Lymphoid Cells (ILC2s) in human allergic airway disease, highlighting their significant contribution to type 2 cytokine production, which was previously attributed primarily to Th2 cells. It details the established epithelial-derived activators like IL-25, IL-33, and TSLP, alongside newly identified cytokine and lipid mediators that influence ILC2 effector functions. The paper positions ILC2s and their mediators as crucial therapeutic targets for allergic airway diseases and discusses the translation of findings from mouse models to human applications.

Summary: This study investigates the exacerbation of chronic murine allergic airway diseases through repeated allergen (OVA) rechallenges, observing increased airway hyperresponsiveness, eosinophilic inflammation, and specific IgE/IgG1. The research found that while CD4+ Th2 cells increased during recall responses, ILC2 numbers remained constant, and both CD4+ Th17 cells and ILC2s were crucial for the allergic recall response. Specifically, the increase in CD4+ Th2 cells enhanced IL-13 production by ILC2s stimulated by IL-25 and IL-33, while ILC2s, in turn, promoted CD4+ Th2 cell proliferation and cytokine production, thereby driving eosinophilic inflammation and goblet cell hyperplasia. The findings suggest a collaborative interaction between ILC2s and CD4+ Th2 cells is key to exacerbating allergic airway disease with an eosinophilic phenotype.

Summary: This review discusses the pathogenesis of ILC2-mediated type 2 airway diseases, such as asthma, which are characterized by uncontrolled type 2 immune responses, elevated IL-4, IL-5, and IL-13 cytokines, eosinophilic inflammation, and tissue remodeling. It highlights that ILC2s, unlike T cells, lack antigen-specific receptors, are tissue-resident, respond to airway epithelium-derived alarmins like TSLP and IL-33 by secreting type 2 cytokines, and can bypass T cell activation and develop corticosteroid resistance. The abstract also notes that current biologics targeting TSLP or IL-4/IL-13 receptors may reduce ILC2 activation, but emphasizes the ongoing need for novel treatments for these conditions.

Summary: This review focuses on Group 2 Innate Lymphoid Cells (ILC2s) as significant contributors to human allergic diseases, challenging traditional views that attributed TH2 cytokine production (IL-4, IL-5, IL-9, IL-13) solely to CD4+T(H)2 cells. The abstract highlights that ILC2s produce high levels of these TH2 cytokines and have been found in various human tissues, suggesting their involvement in conditions like asthma, atopic dermatitis, and gastrointestinal allergic disease. Furthermore, findings from animal models, where ILC2 depletion impacts atopic dermatitis and asthma, support their pathogenic role, with the review aiming to provide mechanistic insights from these models into human allergy and asthma.

Summary: This study investigated the impact of enforced Gata3 expression, a key transcription factor for both T helper 2 (Th2) cells and group 2 innate lymphoid cells (ILC2s), on susceptibility to allergic airway inflammation (AAI) in mice. Using CD2-Gata3 transgenic mice, researchers found that enforced Gata3 expression increased susceptibility to AAI induced by mild allergen exposure, leading to enhanced levels of IL-5 and IL-13. Both ILC2s and Th2 cells were identified as significant cellular sources of these cytokines, with ILC2s showing increased numbers and high IL-33 receptor expression, contributing to early cytokine production. The findings demonstrate that elevated Gata3 activity in these cells is sufficient to boost their activity and promote AAI, even with minimal antigen challenge.

Summary: This review discusses bronchial asthma as a chronic airways inflammatory disease, classifying it into type 2 and non-type 2 phenotypes. It highlights the emerging role of group 2 innate lymphoid cells (ILC2s) in producing classical type 2 cytokines and emphasizes the crucial role of Th2 cells and IL-4 in allergic asthma pathogenesis. The paper reviews evidence on the concept of type 2 inflammation, noting that while IL-13 shares functions with IL-4, it does not induce Th2 cell differentiation. It integrates findings on the cellular and molecular network behind type 2 inflammation, suggesting that adaptive Th2 and innate cell responses, including ILC2s, are integrated systems in the production of IL-4, IL-5, and IL-13, leading to the current understanding of type 2 inflammation.

Summary: This review discusses the significant role of Group 2 Innate Lymphoid Cells (ILC2s) in the pathogenesis of eosinophilic asthma, noting their increased numbers and production of IL-5 and IL-13 in asthmatic airways, particularly in severe cases. While epithelial-derived cytokines are known activators, the review highlights emerging evidence on the Tumor Necrosis Factor Super Family (TNFSF) and its receptors (TNFRSF) as promoters of ILC2 activity, exploring this relationship's implications for severe asthma and airway autoimmune responses.

Summary: This paper explores the link between severe respiratory syncytial virus (RSV) infection in infancy and the increased risk of childhood wheezing and asthma, proposing that airway epithelial cells release alarmins (TSLP, IL-33, HMGB1, IL-25) upon RSV recognition. These alarmins activate innate lymphoid cells 2 (ILC2s), which are identified as innate counterparts of Th2 cells, to produce IL-4, IL-5, and IL-13, thereby promoting airway inflammation and hyperresponsiveness characteristic of RSV bronchiolitis and childhood asthma. The authors suggest that long-term epithelial changes or epigenetic modifications post-RSV infection, as well as RSV-induced gut microbiota alterations, may contribute to increased susceptibility to obstructive lung diseases, highlighting the alarmin-ILC2 interaction as a potential target for prevention and therapy.

Summary: This article reviews the production, function, and clinical applications of IL-33 in respiratory diseases characterized by Type 2 inflammation, such as asthma and COPD. It highlights IL-33 as an epithelial-derived alarm signal that promotes Type 2 inflammation, which is mediated by Type 2 helper T cells (Th2) and Type 2 innate lymphoid cells (ILC2s). The review aims to provide insights into the mechanisms and therapeutic targets for these lung diseases by analyzing them through the lens of Type 2 inflammation and IL-33 signaling.

Summary: This paper reviews the role of airway epithelial cell-derived alarmins, specifically IL-25, IL-33, and TSLP, in initiating lung inflammation. These alarmins are released upon detection of inhaled threats and activate immune cells, contributing to type 2 inflammatory processes characteristic of allergic diseases like asthma. The abstract highlights that blocking TSLP and IL-33 has shown therapeutic benefits in clinical trials and that genetic associations link these alarmins to asthma risk, underscoring their importance as therapeutic targets.

Summary: This study investigated the role of innate lymphoid cells (ILCs) in ozone-induced nonatopic asthma using ILC-sufficient and ILC-deficient mice. While a single ozone exposure caused neutrophilic inflammation and epithelial injury irrespective of ILC presence, repeated ozone exposures induced eosinophilic inflammation and mucous cell metaplasia specifically in ILC-sufficient mice. These repeated exposures also led to increased expression of type 2 immunity and mucus production-related transcripts in ILC-sufficient mice, whereas ILC-deficient mice showed no such pathology or gene expression changes, suggesting ILCs are crucial for developing this ozone-induced asthma phenotype.

Summary: This review explores the role of Group 2 Innate Lymphoid Cells (ILC2s) in the pathogenesis of asthma, particularly when co-occurring with atopic dermatitis (AD), highlighting that dysregulated type 2 immune inflammation is central to both conditions. It emphasizes that ILC2s are key drivers of this inflammation, activated by epithelial alarmins to produce cytokines such as IL-5 and IL-13, which contribute to airway inflammation and hyperresponsiveness in asthma. The paper aims to bridge research findings with clinical practice by discussing ILC2s in asthma, AD, and their combined impact, suggesting that targeting ILC2s could be a promising therapeutic strategy.

Summary: This study investigated the role of type 2 innate lymphoid cells (ILC2s) and T helper 2 (Th2) cells in pollutant-enhanced allergic airway inflammation using a murine model. The researchers found that concomitant exposure to diesel exhaust particles (DEP) and house dust mite (HDM) significantly exacerbated allergic airway inflammation, characterized by increased IL-33, eosinophilia, goblet cell metaplasia, and type 2 cytokine production, with enhanced accumulation of ILC2 and Th2 cells. These inflammatory responses were abolished in Rag2-/- mice and attenuated in Gata-3 haplo-insufficient mice, indicating that dysregulation of ILC2 and Th2 cells impairs these pollutant-enhanced allergic airway responses.

Summary: This review summarizes current knowledge on how signals from the airway epithelium influence the pathology of allergic diseases, from initial allergen contact to Th2 cell responses. It highlights that allergic sensitization involves complex interactions between environmental exposures and genetics, leading to Th2 cell-driven inflammation. Emerging evidence suggests epithelial dysfunction and allergen properties contribute to these inflammatory responses, with epithelial-derived cytokines like TSLP, IL-25, and IL-33 influencing dendritic cells and Th2 effector cells, while a healthy epithelium can mitigate inflammatory T-cell responses to allergens.