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Innate lymphoid cells (ILCs) are a diverse population of lymphocytes classified into natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and ILCregs, broadly following the cytokine secretion and transcription factor profiles of classical T cell subsets. Nonetheless, the ILC lineage does not have rearranged antigen-specific receptors and possesses distinct characteristics. ILCs are found in barrier tissues such as the skin, lungs, and intestines, where they play a role between acquired immune cells and myeloid cells. Within the skin, ILCs are activated by the microbiota and, in turn, may influence the microbiome composition and modulate immune function through cytokine secretion or direct cellular interactions. In particular, ILC3s provide epithelial protection against extracellular bacteria. However, the mechanism by which these cells modulate skin health and homeostasis in response to microbiome changes is unclear. To better understand how ILC3s function against microbiota perturbations in the skin, we propose a role for these cells in response to Cutibacterium acnes, a predominant commensal bacterium linked to the inflammatory skin condition, acne vulgaris. In this article, we review current evidence describing the role of ILC3s in the skin and suggest functional roles by drawing parallels with ILC3s from other organs. We emphasize the limited understanding and knowledge gaps of ILC3s in the skin and discuss the potential impact of ILC3-microbiota crosstalk in select skin diseases. Exploring the dialogue between the microbiota and ILC3s may lead to novel strategies to ameliorate skin immunity.

Group 2 innate lymphoid cells (ILC2s) play a crucial role in the progression of asthma, yet the regulatory mechanisms modulating ILC2 responses in asthma remain underexplored. Human milk oligosaccharides (HMOs), vital non‐nutritive components of breast milk, are known to significantly shape immune system development and influence the incidence of allergic diseases. However, their impact on ILC2‐driven asthma is not fully understood. Our research reveals that dietary HMOs act as potent inhibitors of ILC2 responses and allergic airway inflammation. Treatment with 2′‐fucosyllactose (2'‐FL) and 6′‐sialyllactose (6'‐SL) significantly reduced ILC2‐related airway inflammation induced by papain or Alternaria alternata in mice, evidenced by decreased eosinophil (EOS) infiltration and lower IL‐5 and IL‐13 levels in BALF. Notably, while ILC2 expresses HMO receptors, HMO did not act directly on ILC2 but potentially modulated their activity through alterations in gut microbiota derived SCFAs. HMO treatments alleviated airway inflammation in SCFA‐dependent manners, with SCFA depletion or receptor blocking reversing these beneficial effects. This study reveals the potential of dietary HMOs in managing asthma through modulation of ILC2 activity and the gut‐lung axis, proposing a new therapeutic avenue that utilises the immunomodulatory capacities of nutritional components to combat respiratory diseases. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion The role of lung group 2 innate lymphoid cell (ILC2) activation in allergic asthma is increasingly established. However, the regulatory mechanisms underlying hypoxia‐inducible factor‐1α (HIF‐1α)‐mediated glycolysis in ILC2‐mediated allergic airway inflammation remain unclear.To investigate the role of the HIF‐1α/glycolysis axis in ILC2‐mediated allergic airway inflammation.Glycolysis and HIF‐1α inhibitors were used to identify their effect on the function and glucose metabolism of mouse and human ILC2s in vivo and vitro. Blocking glycolysis and HIF‐1α in mice under interleukin‐33 (IL‐33) stimulation were performed to test ILC2 responses. Conditional HIF‐1α‐deficient mice were used to confirm the specific role of HIF‐1α in ILC2‐driven airway inflammation models. Transcriptomic, metabolic, and chromatin immunoprecipitation analyses were performed to elucidate the underlying mechanism.HIF‐1α is involved in ILC2 metabolism and is crucial in allergic airway inflammation. Single‐cell sequencing data analysis and qPCR confirmation revealed a significant upregulation of glycolysis‐related genes, particularly HIF‐1α, in murine lung ILC2s after IL‐33 intranasal administration or injection. Treatment with the glycolysis inhibitor 2‐deoxy‐D‐glucose (2‐DG) and the HIF‐1α inhibitor 2‐methoxyestradiol (2‐ME) abrogated inflammation by suppressing ILC2s function. Conditional HIF‐1α‐deficient mice showed reduced ILC2 response and airway inflammation induced upon IL‐33 or house dust mite (HDM) stimulation. Transcriptome and metabolic analyses revealed significantly impaired glycolysis in lung ILC2s in conditional HIF‐1α knockout mice compared to that in their littermate controls. Chromatin immunoprecipitation results confirmed the transcriptional downregulation of glycolysis‐related genes in HIF‐1α‐knockout and 2‐DG‐treated mice. Furthermore, impaired HIF‐1α/glycolysis axis activation is correlated with downregulated ILC2 in patients with asthma.The HIF‐1α/glycolysis axis is critical for controlling ILC2 responses in allergic airway inflammation and has potential immunotherapeutic value in asthma. [ABSTRACT FROM AUTHOR]

The correlation between liver disease and the progression of ulcerative colitis (UC) has remained elusive. In this study, it demonstrates that liver injury is intricately linked to the heightened severity of UC in patients, and causes more profound intestinal damage during DSS‐induced colitis in mice. Metabolomics analysis of plasma from liver cirrhosis patients shows liver injury compromising nicotinamide supply for NAD+ biosynthesis in the intestine. Subsequent investigation identifies intestinal group 2 innate lymphoid cells (ILC2s) are responsible for liver injury‐exacerbated colitis. Reconstitution of ILC2s or the restoration of NAD+ metabolism proves effective in relieving liver injury‐aggravated experimental colitis. Mechanistically, the NAD+ salvage pathway regulates gut ILC2s in a cell‐intrinsic manner by supporting the generation of succinate, which fuels the electron transport chain to sustaining ILC2s function. This research deepens the understanding of cellular and molecular mechanisms in liver disease‐UC interplay, identifying a metabolic target for innovative treatments in liver injury‐complicated colitis. [ABSTRACT FROM AUTHOR]

Antigen-specific humoral responses are orchestrated through complex interactions among immune cells in lymphoid tissues, including the collaboration between B cells and T follicular helper (Tfh) cells. Accumulating evidence indicates a crucial role for interleukin-9 (IL-9) in the formation of germinal centers (GCs), enhancing the generation of class-switched high-affinity antibodies. However, the exact function of IL-9 in Tfh cell regulation remains unclear. In this study, we examined the humoral immune responses of CD4Cre/+Il9rafl/fl mice, which lack an IL-9-specific receptor in Tfh cells. Upon intraperitoneal immunization with sheep red blood cells (SRBCs), CD4Cre/+Il9rafl/fl mice displayed diminished levels of SRBCspecific IgG antibodies in their sera, along with reduced levels of GC B cells and plasma cells. Notably, Il9ra-deficient Tfh cells in the spleen exhibited decreased expression of their signature molecules such as B-cell lymphoma 6, C-X-C chemokine receptor 5, IL-4, and IL-21 compared to control mice. In models of allergic asthma induced by house dust mite (HDM) inhalation, CD4Cre/+Il9rafl/fl mice failed to elevate serum levels of HDM-specific IgE and IgG. This was accompanied by reductions in Tfh cells, GC B cells, and plasma cells in mediastinal lymph nodes. Furthermore, group 2 innate lymphoid cells (ILC2s) were identified as producers of IL-9 under immunizing conditions, possibly induced by leukotrienes released by activated IgD+ B cells around the T-B border. These observations may indicate the critical role of IL-9 receptor signaling in the activation of Tfh cells, with ILC2s potentially capable of supplying IL-9 in organized lymphoid tissues. [ABSTRACT FROM AUTHOR]

The immune system recognizes a multitude of innocuous antigens from food and intestinal commensal microbes toward which it orchestrates appropriate, non-inflammatory responses. This process requires antigen-presenting cells (APCs) that induce T cells with either regulatory or effector functions. Compromised APC function disrupts the T cell balance, leading to inflammation and dysbiosis. Although their precise identities continue to be debated, it has become clear that multiple APC lineages direct the differentiation of distinct microbiota-specific CD4+ T cell programs. Here, we review how unique APC subsets instruct T cell differentiation and function in response to microbiota and dietary antigens. These discoveries provide new opportunities to investigate T cell-APC regulatory networks controlling immune homeostasis and perturbations associated with inflammatory and allergic diseases. Although the precise identities of the APCs that induce peripheral Treg cells and most effector T cell subsets continue to be debated, what is clear is that the microbiota direct the differentiation of distinct CD4+ T cell programs by delivering antigens to multiple APCs that are dedicated to unique functions in their instruction of T cells and may participate in regulatory networks to achieve homeostasis. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell (HSC)-independent lymphopoiesis has been elucidated in murine embryos. However, our understanding regarding human embryonic counterparts remains limited. Here, we demonstrated the presence of human yolk sac-derived lymphoid-biased progenitors (YSLPs) expressing CD34 , IL7R , LTB , and IRF8 at Carnegie stage 10, much earlier than the first HSC emergence. The number and lymphopoietic potential of these progenitors were both significantly higher in the yolk sac than the embryo proper at this early stage. Importantly, single-cell/bulk culture and CITE-seq have elucidated the tendency of YSLP to differentiate into innate lymphoid cells and dendritic cells. Notably, lymphoid progenitors in fetal liver before and after HSC seeding displayed distinct transcriptional features, with the former closely resembling those of YSLPs. Overall, our data identified the origin, potential, and migratory dynamics of innate lymphoid-biased multipotent progenitors in human yolk sac before HSC emergence, providing insights for understanding the stepwise establishment of innate immune system in humans. [Display omitted] • Progenitors with non-NK lymphoid potential exist in human yolk sac before HSC onset • Human yolk sac lymphoid progenitors before HSC emergence show ILC and DC potential • ILC potential before HSC onset is stronger in human yolk sac than in embryo proper • Early fetal liver lymphoid progenitors share characteristics with those from yolk sac Liu et al. demonstrated the presence of yolk sac-derived lymphoid progenitors expressing IL7R and IRF8 well before HSC emergence in human embryos, which showed differentiation bias toward innate lymphoid cells and dendritic cells. They shared transcriptional profiles with lymphoid progenitors in the fetal liver before HSC colonization. [ABSTRACT FROM AUTHOR]

AbstractCommon variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency (PID) characterized by an impaired immunoglobulin production, in association with an increased susceptibility to infections and a diversity of clinical manifestations. This narrative review summarizes immunophenotypic abnormalities in CVID patients and their relevance for diagnosis and disease classification. A comprehensive search across four databases - PubMED, Web of Science, EMBASE and Google Scholar – yielded 170 relevant studies published between 1988 and April 31, 2023. Over the past decades, the role of immunophenotyping in CVID diagnosis has become evident by identifying “hallmark” immunophenotypic aberrancies in patient subsets, with some now integrated in the consensus diagnostic criteria. Furthermore, the role of immunophenotyping in subclassifying CVID in relation to clinical presentation and prognosis has been extensively studied. Certain immunophenotypic patterns consistently correlate with clinical manifestations and/or subsets of CVID, particularly those associated with noninfectious complications (i.e. low switched memory B cells, shifts in follicular helper T cell subsets, low naïve CD4+ T cells, low regulatory T cells, and expansion of CD21low B cells, often associated with autoimmunity and/or splenomegaly). Also, efforts to associate subset levels of innate immune cells, such as Natural Killer (NK) cells, invariant (i)NKT cells, innate lymphoid cells (ILCs), and dendritic cells (DCs) to CVID complications are evident albeit in a lesser degree. However, inconsistencies regarding the role of flow cytometry in classification and prognosis persist, reflecting the disease complexity, but probably also cohort variations and methodological differences between published studies. This underscores the need for collaborative efforts to integrate emerging concepts, such as standardized flow cytometry and computational tools, for a more precise CVID classification approach. Additionally, recent studies suggest a potential value of (epi)genetic-based molecular assays to this effort. [ABSTRACT FROM AUTHOR]

Interleukin (IL)‐5 is the key cytokine in the maturation, activation, proliferation, migration and survival of eosinophils, which are key effector cells in many upper and lower airway diseases. Through its effects on eosinophils, IL‐5 indirectly contributes to various pathophysiological processes including tissue damage, repair and remodelling. Understanding the importance of IL‐5 in eosinophil‐associated diseases led to the development of anti‐IL‐5 therapies, which provide clinical benefits across a range of conditions. However, recent evidence suggests that eosinophil‐depletion alone may not account for all of the therapeutic effects of anti‐IL‐5 therapy and that IL‐5 may also contribute to disease independently of its effects on eosinophils. Indeed, evidence from ex vivo studies and targeted therapy in vivo demonstrates that IL‐5 and its inhibition affects a much broader range of cells beyond eosinophils, including epithelial cells, plasma cells, mast cells, basophils, neutrophils, type 2 innate lymphoid cells, T regulatory cells and fibroblasts. This review will provide an update on the evidence supporting the breadth of IL‐5 biology relevant to disease pathogenesis beyond eosinophil‐associated inflammation, where there is a need for additional insight, and the clinical implications of a more central role of IL‐5 in type 2 inflammation. [ABSTRACT FROM AUTHOR]

Background: Intravenous immunoglobulin (IVIg) has been used for almost 40 years in the treatment of autoimmune and systemic inflammatory diseases. Numerous cells are involved in the innate immune response, including monocytes/macrophages, neutrophils, dendritic cells, mast cells, basophils, eosinophils, natural killer cells, and innate lymphoid cells. Many studies have investigated the mechanisms by which IVIg down-modulates inflammatory and autoimmune processes of innate immune cells. However, questions remain regarding the precise mechanism of action in autoimmune or inflammatory conditions. The aim of this work was to review the immunomodulatory effect of IVIg on only human innate immune cells. A narrative review approach was chosen to summarize key evidence on the immunomodulatory effects of commercially available and unmodified IVIg on human innate immune cells. Summary: Numerous different immunomodulatory effects of IVIg have been reported, with some very different effects depending on the immune cell type and disease. Several limitations of the different studies were identified. Of the 77 studies identified and reviewed, 29 (37.7%) dealt with autoimmune or inflammatory diseases. Otherwise, the immunomodulatory effects of IVIg were studied only in healthy donors using an in vitro experimental approach. Some of the documented effects showed disease-specific effects, such as in Kawasaki disease. Various methodological limitations have also been identified that may reduce the validity of some studies. Key Message: As further insights have been gained into the various inflammatory cascades activated in immunological diseases, interesting insights have also been gained into the mechanism of action of IVIg. We are still far from discovering all the immunomodulatory mechanisms of IVIg. [ABSTRACT FROM AUTHOR]

The article in MedComm discusses the impact of the androgen-type 2 innate lymphoid cells-dendritic cell axis on sex-associated differences in skin immune responses. The study by Chi et al. reveals that sex hormones and the microbiota influence tissue immune set points and dendritic cell network strength, leading to disparities in susceptibility to diseases between males and females. The research highlights the role of androgen signaling in regulating immune responses and emphasizes the potential for gender-tailored therapeutic approaches in various diseases. The findings underscore the complex interplay between sex hormones, microbiota, and immune cells in shaping tissue immune responses and DC network resilience, offering insights into sex differences in disease susceptibility. [Extracted from the article]

The mucosal immune system is a critical first line of defense to infectious diseases, as many pathogens enter the body through mucosal surfaces, disrupting the balanced interactions between mucosal cells, secretory molecules, and microbiota in this challenging microenvironment. The mucosal immune system comprises of a complex and integrated network that includes the gut-associated lymphoid tissues (GALT). One of its primary responses to microbes is the secretion of IgA, whose role in the mucosa is vital for preventing pathogen colonization, invasion and spread. The mechanisms involved in these key responses include neutralization of pathogens, immune exclusion, immune modulation, and cross-protection. The generation and maintenance of high affinity IgA responses require a delicate balance of multiple components, including B and T cell interactions, innate cells, the cytokine milieu (e.g., IL-21, IL-10, TGF-b), and other factors essential for intestinal homeostasis, including the gut microbiota. In this review, we will discuss the main cellular components (e.g., T cells, innate lymphoid cells, dendritic cells) in the gut microenvironment as mediators of important effector responses and as critical players in supporting B cells in eliciting and maintaining IgA production, particularly in the context of enteric infections and vaccination in humans. Understanding the mechanisms of humoral and cellular components in protection could guide and accelerate the development of more effective mucosal vaccines and therapeutic interventions to efficiently combat mucosal infections. [ABSTRACT FROM AUTHOR]

Rationale. The progressive decline in lung function observed in asthma is attributed to persistent type 2 airway inflammation and associated airway remodeling. While various immune cells are involved in localized type 2 airway inflammation, whether these reflect the presence of airway obstruction due to persistent type 2 airway inflammation remains unclear. This study aimed to explore whether the proportions of immune cells in peripheral blood indicate the presence of type 2 inflammation and airway obstruction in asthmatics. Materials and Methods. Using flow cytometry, we identified and quantified Group 2 innate lymphocytes, T helper 2 cells, follicular helper T cells, and T helper 17 cells in peripheral blood samples from 49 individuals with asthma. We then conducted cross‐sectional analyses to assess relationships between levels of these immune cells and lung function parameters, including the percentage predicted forced expiratory volume in 1 s (%FEV1). We also examined correlations between the proportions of immune cells and type 2 biomarkers. Results. Proportions of CXCR5+ follicular helper T cells in human peripheral blood, as opposed to Group 2 innate lymphoid cells (ILC2) or T helper 2 cells, were significantly higher in cases with %FEV1 < 80% compared to those with %FEV1 ≥ 80%. Further, these proportions correlated negatively with %FEV1 and positively with blood eosinophil counts. Conclusions. The proportion of circulating follicular helper T cells, but not T helper 2 cells or Group 2 innate lymphoid cells, may reflect the presence of airway obstruction caused by persistent type 2 inflammation. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is a condition with limited treatment options. This study investigates the potential use of mesenchymal stem cell (MSC) nanovesicles as a novel therapy for AR. Specifically, the study explores the underlying mechanisms of MSC nanovesicle therapy by targeting dendritic cells (DCs). The researchers fabricated DC-targeted P-D2-EVs nanovesicles and characterized their properties. Transcriptomic sequencing and single-cell sequencing analyses were performed to study the impact of P-D2-EVs on AR mice, identifying core genes involved in the treatment. In vitro cell experiments were conducted to validate the effects of P-D2-EVs on DC metabolism, Th2 differentiation, and ILC2 activation. The results showed that P-D2-EVs efficiently targeted DCs. Transcriptomic sequencing analysis revealed differential expression of 948 genes in nasal tissue DCs of mice treated with P-D2-EVs. Single-cell sequencing further revealed that P-D2-EVs had inhibitory effects on DC activation, Th2 differentiation, and ILC2 activation, with Fut1 identified as the core gene. Validation experiments demonstrated that P-D2-EVs improved IL10 metabolism in DCs by downregulating Fut1 expression, thereby suppressing Th2 differentiation and ILC2 activation. Animal experiments confirmed the inhibitory effects of P-D2-EVs and their ability to ameliorate AR symptoms in mice. The study suggests that P-D2-EVs reshape DC metabolism and suppress Th2 differentiation and ILC2 activation through the inhibition of the Fut1/ICAM1/P38 MAPK signaling pathway, providing a potential therapeutic approach for AR. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is an autoimmune disease with a strong chronic inflammatory component. One possible strategy for the treatment of T1D is to stimulate the regulatory arm of the immune response, i.e. to promote the function of tolerogenic dendritic cells (tolDC) and regulatory T cells (Treg). Since both cell types have been shown to be responsive to the aryl hydrocarbon receptor (AHR) activation, we used a recently characterized member of a new class of fluorescent AHR ligands, AGT-5, to modulate streptozotocin-induced T1D in C57BL/6 mice. Prophylactic oral administration of AGT-5 reduced hyperglycemia and insulitis in these mice. Phenotypic and functional analysis of cells in the pancreatic infiltrates of AGT-5-treated mice (at the early phase of T1D) revealed a predominantly anti-inflammatory environment, as evidenced by the upregulation of tolDC and Treg frequency, while CD8+ cell, Th1 and Th17 cells were significantly reduced. Similarly, AGT-5 enhanced the proportion of Treg and tolDC in small intestine lamina propria and suppressed the activation status of antigen-presenting cells through downregulation of co-stimulatory molecules CD40, CD80 and CD86. The expression levels of Cyp1a1, controlled by the AHR, were increased in CD4+, CD8+ and Treg, confirming the AHR-mediated effect of AGT-5 in these cells. Finally, AGT-5 stimulated the function of regulatory cells in the pancreatic islets and lamina propria by upregulating indoleamine 2,3-dioxigenase 1 (IDO1) in tolDC. These findings were supported by the abrogation of AGT-5-mediated in vitro effects on DC in the presence of IDO1 inhibitor. AGT-5 also increased the expression of CD39 or CD73 ATP-degrading ectoenzymes by Treg. The increase in Treg is further supported by the upregulated frequency of IL-2-producing type 3 innate lymphoid cells (ILC3) in the lamina propria. Anti-inflammatory effects of AGT-5 were also validated on human tonsil cells, where in vitro exposure to AGT-5 increased the proportion of immunosuppressive dendritic cells and ILC3. These results suggest that AGT-5, by stimulating AHR, may promote a general immunosuppressive environment in the pancreas and small intestine lamina propria at the early phase of disease, and thereby inhibit the severity of T1D in mice. [ABSTRACT FROM AUTHOR]

Epithelial-derived IL-33 (Interleukin-33), as a member of alarm signals, is a chemical substance produced under harmful stimuli that can promote innate immunity and activate adaptive immune responses. Type 2 inflammation refers to inflammation primarily mediated by Type 2 helper T cells (Th2), Type 2 innate lymphoid cells (ILC2), and related cytokines. Type 2 inflammation manifests in various forms in the lungs, with diseases such as asthma and chronic obstructive pulmonary disease chronic obstructive pulmonary disease (COPD) closely associated with Type 2 inflammation. Recent research suggests that IL-33 has a promoting effect on Type 2 inflammation in the lungs and can be regarded as an alarm signal for Type 2 inflammation. This article provides an overview of the mechanisms and related targets of IL-33 in the development of lung diseases caused by Type 2 inflammation, and summarizes the associated treatment methods. Analyzing lung diseases from a new perspective through the alarm of Type 2 inflammation helps to gain a deeper understanding of the pathogenesis of these related lung diseases. This, in turn, facilitates a better understanding of the latest treatment methods and potential therapeutic targets for diseases, with the expectation that targeting lL-33 can propose new strategies for disease prevention. [ABSTRACT FROM AUTHOR]

RORγt+ group 3 innate lymphoid cells (ILC3s), the innate counterpart of Th17 cells, are enriched in the mucosal area and lymphoid tissues. ILC3s interact with a variety of cells through their effector molecules and play an important role in the host defense against a spectrum of infections. Recent studies suggest that the extensive crosstalk between ILC3s and adaptive immune cells, especially T cells, is essential for maintaining tissue homeostasis. Here we discuss recent advances in the crosstalk between ILC3s and adaptive immune responses in multiple tissues and diseases. Understanding how ILC3s engage with adaptive immune cells will enhance our comprehension of diseases and facilitate the identification of novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Intestinal tuft cells are critical for anti-helminth parasite immunity because they produce IL-25, which triggers IL-13 secretion by activated group 2 innate lymphoid cells (ILC2s) to expand both goblet and tuft cells. We show that epithelial Elp3, a tRNA-modifying enzyme, promotes tuft cell differentiation and is consequently critical for IL-25 production, ILC2 activation, goblet cell expansion and control of Nippostrongylus brasiliensis helminth infection in mice. Elp3 is essential for the generation of intestinal immature tuft cells and for the IL-13-dependent induction of glycolytic enzymes such as Hexokinase 1 and Aldolase A. Importantly, loss of epithelial Elp3 in the intestine blocks the codon-dependent translation of the Gator1 subunit Nprl2, an mTORC1 inhibitor, which consequently enhances mTORC1 activation and stabilizes Atf4 in progenitor cells. Likewise, Atf4 overexpression in mouse intestinal epithelium blocks tuft cell differentiation in response to intestinal helminth infection. Collectively, our data define Atf4 as a negative regulator of tuft cells and provide insights into promotion of intestinal type 2 immune response to parasites through tRNA modifications. Synopsis: Epithelial host response mechanisms against parasites remain poorly understood. This work identifies the tRNA-modifying enzyme Elp3 as a critical promoter of intestinal tuft cell expansion and type 2 immunity in mice, mounting protection against helminth infection. Elp3 is required for the anti-helminth immune response in the intestine. Epithelial Elp3 depletion inhibits tuft cell differentiation. Elp3 deficiency decreases mRNA translation of mTORC1 inhibitor Nprl2, potentiating mTORC1-Atf4 signaling. Atf4 overexpression in the intestinal epithelium results in incomplete response to helminth infections due to defective tuft cell amplification. tRNA-modifying enzyme Elp3 is required for protective type 2 immunity in the intestinal epithelium upon helminth infection, supporting tuft cell expansion and goblet cell function. [ABSTRACT FROM AUTHOR]

Rationale: In asthma, sputum group 2 innate lymphoid cells (ILC2s) are activated within 7 hours after allergen challenge. Neuroimmune interactions mediate rapid host responses at mucosal interfaces. In murine models of asthma, lung ILC2s colocalize to sensory neuronal termini expressing the neuropeptide neuromedin U (NMU), which stimulates type 2 (T2) cytokine secretion by ILC2s, with additive effects to alarmins in vitro. Objectives: To investigate the effect of the NMU/NMUR1 (NMU receptor 1) axis on early activation of ILC2s in asthma. Methods: Subjects with mild asthma (n = 8) were enrolled in a diluent-controlled allergen inhalation challenge study. Sputum ILC2 expression of NMUR1 and T2 cytokines was enumerated by flow cytometry, and airway NMU levels were assessed by ELISA. This was compared with samples from subjects with moderate to severe asthma (n = 9). Flow sort–purified and ex vivo–expanded ILC2s were used for functional assays and transcriptomic analyses. Measurements and Main Results: Significant increases in sputum ILC2s expressing NMUR1 were detected 7 hours after allergen versus diluent challenge whereby the majority of NMUR1+ ILC2s expressed IL-5/IL-13. Sputum NMUR1+ ILC2 counts were significantly greater in mild versus moderate to severe asthma, and NMUR1+ ILC2s correlated inversely with the dose of inhaled corticosteroid in the latter group. Coculturing with alarmins upregulated NMUR1 in ILC2s, which was attenuated by dexamethasone. NMU-stimulated T2 cytokine expression by ILC2s, maximal at 6 hours, was abrogated by dexamethasone or specific signaling inhibitors for mitogen-activated protein kinase 1/2 and phosphoinositol 3-kinase but not the IL-33 signaling moiety MyD88 in vitro. Conclusions: The NMU/NMUR1 axis stimulates rapid effects on ILC2s and may be an important early activator of these cells in eosinophilic inflammatory responses in asthma. [ABSTRACT FROM AUTHOR]

Introduction: Group 3 innate lymphoid cells (ILC3s) are enriched in the intestinal mucosa and play important roles in host defense against infection and inflammatory diseases. Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD+)- dependent deacetylase and has been shown to control intestinal epithelial cell differentiation and survival. However, the role of SIRT6 in ILC3s remains unknown. Methods: To investigate the role of SIRT6 in gut ILC3s, we generated SIRT6 conditional knockout mice by crossing Rorccre and Sirt6flox/flox mice. Cell number and cytokine production was examined using flow cytometry. Citrobacter rodentium infection and dextran sodium sulfate-induced colitis models were used to determine the role of SIRT6 in gut defense. RT-qPCR, flow cytometry and immunohistochemistry were used to assess the intestinal inflammatory responses. Results: Here we show that SIRT6 inhibits IL-22 expression in intestinal ILC3s in a cell-intrinsic manner. Deletion of SIRT6 in ILC3s does not affect the cell numbers of total ILC3s and subsets, but results in increased IL-22 production. Furthermore, ablation of SIRT6 in ILC3s protects mice against Citrobacter rodentium infection and dextran sodium sulfate-induced colitis. Our results suggest that SIRT6 may play a role in ILC3 function by regulating gut immune responses against bacterial infection and inflammation. Discussion: Our finding provided insight into the relation of epigenetic regulators with IL-22 production and supplied a new perspective for a potential strategy against inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Immune memory has been expanded to group 2 innate lymphoid cells (ILC2s), but the cellular and molecular bases remain incompletely understood. Based on house dust mite (HDM)-induced mice asthma models and human samples, we applied flow cytometry, parabiosis, in vivo imaging and adoptive transplantation to confirm the persistence, migration and function of CD45+lineage–CD90.2+NK1.1–NKp46–ST2–KLRG1+IL-17RB+ memory-like ILC2s (ml-ILC2s). Regulated by CCR9/CCL25 and S1P signaling, ml-ILC2s reside in the lamina propria of small intestines (siLP) in asthma remission, and subsequently move to airway upon re-encountering antigens or alarmins. Furthermore, ml-ILC2s possess properties of longevity, potential of rapid proliferation and producing IL-13, and display transcriptional characteristics with up-regulation of Tox and Tcf-7. ml-ILC2s transplantation restore the asthmatic changes abrogated by Tox and Tcf7 knockdown. Our data identify siLP ml-ILC2s as a memory-like subset, which promotes asthma relapse. Targeting TCF-1 and TOX might be promising for preventing asthma recurrence. TCF1 and TOX have been shown to be important in T memory cell formation. Here the authors show that TCF1 and TOX contribute to the regulation and persistence of memory-like ILC2 cells in mouse asthma models and persons with asthma. [ABSTRACT FROM AUTHOR]

Innate lymphoid cells (ILCs) are critical in maintaining tissue homeostasis, and during infection and inflammation. Here we identify, by using combinatorial reporter mice, a rare ILC progenitor (ILCP) population, resident to the small intestinal lamina propria (siLP) in adult mice. Transfer of siLP-ILCP into recipients generates group 1 ILCs (including ILC1 and NK cells), ILC2s and ILC3s within the intestinal microenvironment, but almost exclusively group 1 ILCs in the liver, lung and spleen. Single cell gene expression analysis and high dimensional spectral cytometry analysis of the siLP-ILCPs and ILC progeny indicate that the phenotype of the group 1 ILC progeny is also influenced by the tissue microenvironment. Thus, a local pool of siLP-ILCP can contribute to pan-ILC generation in the intestinal microenvironment but has more restricted potential in other tissues, with a greater propensity than bone marrow-derived ILCPs to favour ILC1 and ILC3 production. Therefore, ILCP potential is influenced by both tissue of origin and the microenvironment during development. This may provide additional flexibility during the tuning of immune reactions. The small intestinal lamina propria is rich in innate lymphoid cells, which are important contributors of mucosal immunity. Here authors identify a small progenitor cell population that can develop into all types of innate lymphoid cells in their intestinal microenvironment but their developmental potential becomes more restricted when placed into other tissues, such as liver, lung or spleen. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a multiorgan granulomatous disease that lacks diagnostic biomarkers and targeted treatments. Using blood and skin from patients with sarcoid and non-sarcoid skin granulomas, we discovered that skin granulomas from different diseases exhibit unique immune cell recruitment and molecular signatures. Sarcoid skin granulomas were specifically enriched for type 1 innate lymphoid cells (ILC1s) and B cells and exhibited molecular programs associated with formation of mature tertiary lymphoid structures (TLSs), including increased CXCL12/CXCR4 signaling. Lung sarcoidosis granulomas also displayed similar immune cell recruitment. Thus, granuloma formation was not a generic molecular response. In addition to tissue-specific effects, patients with sarcoidosis exhibited an 8-fold increase in circulating ILC1s, which correlated with treatment status. Multiple immune cell types induced CXCL12/CXCR4 signaling in sarcoidosis, including Th1 T cells, macrophages, and ILCs. Mechanistically, CXCR4 inhibition reduced sarcoidosis-activated immune cell migration, and targeting CXCR4 or total ILCs attenuated granuloma formation in a noninfectious mouse model. Taken together, our results show that ILC1s are a tissue and circulating biomarker that distinguishes sarcoidosis from other skin granulomatous diseases. Repurposing existing CXCR4 inhibitors may offer a new targeted treatment for this devastating disease. [ABSTRACT FROM AUTHOR]

Type-3 innate lymphoid cell (ILC3) differentiate into lymphocyte progenitor cells and widely distributed in body, serving as a bridge between innate immunity and adaptive immunity. Previous studies believed that ILC3 was mainly involved in intesti‑ nal immune regulation, however, the latest studies have shown that, in addition to its role in intestinal diseases, ILC3 can also partici‑ pate in occurrence and development of a variety of chronic inflammatory diseases. This article reviews role of ILC3 in chronic inflamma‑ tory diseases. [ABSTRACT FROM AUTHOR]

Mucosal immunity and trained innate immunity of the gut play a pivotal role in maintaining intestinal homeostasis and defending against microbial pathogens. This review provides an overview of the mechanisms underlying mucosal immunity and the concept of trained innate immunity in the gut. We discuss the interaction between gut microbiota and the host immune system, highlighting the role of epithelial cells, dendritic cells, and innate lymphoid cells, as well as the novel concept of trained innate immunity and its role in perpetuating or attenuating gut inflammation. We also comment on the current models for investigating mucosal immunity, their limitations, and how they can be overcome. Additionally, we explore the potential therapeutic implications of modulating mucosal immunity and trained innate immunity in gastrointestinal diseases. Only by elucidating the mechanisms underlying mucosal immunity and the concept of trained innate immunity, innovative approaches to modulate immune responses and restore intestinal homeostasis in the context of gastrointestinal disorders could be implemented. [ABSTRACT FROM AUTHOR]

This article discusses the role of IL-33, an alarmin cytokine, in regulating mast cell responses during food allergy. The IL-33 receptor, ST2, is expressed on mast cells, and genetic variations in the IL-33/ST2 axis are associated with disease susceptibility. The study used a mouse model of food allergy and found that IL-33 is critical for inducing mast cell responses to food antigens. Mice lacking ST2 showed decreased diarrhea, mast cell accumulation, and mast cell activation compared to wild-type mice. The study also found that IL-4 plays a role in mediating mast cell responses, as treatment with IL-4 reversed the attenuated mast cell activation in ST2-deficient mice. These findings provide insights into the potential interplay between IL-33 and IL-4 in the treatment of allergic diseases. [Extracted from the article]

This article explores the relationship between house dust mites (HDM) and asthma. It discusses the role of innate immunity in the generation of specific IgE antibodies, inflammation, and bronchial remodeling. The article highlights the importance of HDM allergens in inducing type 2 bronchial inflammation and discusses new studies that show significant associations between sensitization to HDM allergens and asthma. The article also mentions case-control studies that have found associations between specific HDM allergens and asthma. Overall, the article emphasizes the importance of innate immunity and the need for further research in understanding the pathogenesis and management of asthma related to HDM. [Extracted from the article]

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is associated with high levels of cysteinyl leukotrienes, prostaglandin D2, and low levels of prostaglandin E2. Further, 15-hydroxyeicosatetraenoic acid (15-HETE) levels may have predictive value in therapeutic outcomes of aspirin desensitization. Accumulation of nasal group 2 innate lymphoid cells (ILC2s) has been demonstrated during COX-1 inhibition in AERD, although the relationships between tissue ILC2 accumulation, reaction symptom severity, and novel lipid biomarkers are unknown. OBJECTIVE: We sought to determine whether novel lipid mediators are predictive of nasal ILC2 accumulation and symptom scores during COX-1 inhibitor challenge in patients with AERD. METHODS: Blood and nasal scraping samples from patients with AERD were collected at baseline and COX-1 inhibitor reaction and then processed for flow cytometry for nasal ILC2s and serum for lipidomic analysis. RESULTS: Eight patients with AERD who were undergoing aspirin desensitization were recruited. Of the 161 eicosanoids tested, 42 serum mediators were detected. Baseline levels of 15-HETE were negatively correlated with the change in numbers of airway ILC2s (r = -0.6667; P = .0428). Docosahexaenoic acid epoxygenase metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) was positively correlated with both changes in airway ILC2s (r = 0.7143; P = .0305) and clinical symptom scores (r = 0.5000; P = .0081). CONCLUSION: Low levels of baseline 15-HETE predicted a greater accumulation of airway ILC2s in patients with AERD who were receiving COX-1 inhibition. Further, increases in the cytochrome P pathway metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) were associated with increased symptoms and nasal ILC2 accumulation. Future studies to assess how these mediators might control ILC2s may improve the understanding of AERD pathogenesis.

This article examines the characteristics of patients with atopic dermatitis (AD) who were either untreated or treated with the drug dupilumab. The study found that the count of innate lymphoid cells (ILCs) and their subsets differed in AD patients with and without dupilumab therapy, with significant changes observed in patients without therapy. The severity of AD was not significantly related to the count of ILC cells and their subsets. The article also discusses the terms of the Creative Commons Attribution-NonCommercial License, which allows for the unrestricted non-commercial use, distribution, and reproduction of a work, as long as the original work is properly cited. [Extracted from the article]

Background: Sepsis is a life-threatening condition triggered by uncontrolled immune responses to infection, leading to widespread inflammation, tissue damage, organ dysfunction, and potentially death. The liver plays a crucial role in the immune response during sepsis, serving as a major site for immune cell activation and cytokine production. Liver type 1 innate lymphoid cells (ILCs) consist of NK cells and ILC1s. They maintain the local immune microenvironment by directly eliminating target cells and secreting cytokines. However, the specific roles and pathological changes of liver-resident NK cells and ILC1s during sepsis remain poorly understood. Results: This study aims to investigate the pathological changes of NK cells and ILC1s, which might contribute the dysfunction of liver. Sepsis mouse model was established by cecal ligation and puncture (CLP). Mouse immune cells from liver were isolated, and the surface makers, gene expression profiles, cytokine response and secretion, and mitochondrial function of NK (Natural Killer) cells and ILC1s (Innate Lymphoid Cell 1) were analyzed. A significant decrease in the number of mature NK cells was observed in the liver after CLP. Furthermore, the secretion of interferon-gamma (IFN-γ) was found to be reduced in spleen and liver NK cells when stimulated by IL-18. Mitochondrial activities in both liver NK cells and ILC1 were found to be increased during sepsis, suggesting an enhanced metabolic response in these cells to combat the infection. However, despite this heightened activity, liver NK cells exhibited a decreased level of cytotoxicity, which might impact their ability to target infected cells effectively. RNA sequencing supported and provided the potential mechanisms for the proinflammatory effects and exhaustion like phenotypes of liver NK cells. Conclusions: Sepsis induces dysfunction and exhaustion-like phenotypes in liver NK cells and ILC1, which might further impair other immune cells and represent a potential therapeutic target for sepsis. [ABSTRACT FROM AUTHOR]

Summary Natural killer (NK) cells are innate immune effectors whose functions rely on receptors binding cytokines, recognizing self‐molecules, or detecting danger signals expressed by virus‐infected or tumor cells. The potent cytotoxic potential makes NK cells promising candidates for cancer immunotherapy. To enhance their activity strategies include cytokine administration, blocking of immune checkpoints, and designing of antibody‐based NK cell engagers (NKCEs). NKCEs represent a cutting‐edge approach to cancer therapy: they strengthen the NK‐to‐target cell interactions and optimize tumor killing, possibly overcoming the immunosuppressive tumor microenvironment. NK cells belong to the innate lymphoid cells (ILCs) and are categorized into different subsets also including cells with a memory‐like phenotype: this complexity needs to be explored in the context of cancer immunotherapy, particularly when designing NKCEs. Two strategies to enhance NK cell activity in cancer patients can be adopted: activating patients' own NK cells versus the adoptive transfer of ex vivo activated NK cells. Furthermore, the capability of NKCEs to activate γδ T cells could have a significant synergistic effect in immunotherapy. [ABSTRACT FROM AUTHOR]

Respiratory failure occurs more frequently after thoracic surgery than abdominal surgery. Although the etiology for this complication is frequently attributed to underlying lung disease present in patients undergoing thoracic surgery, this notion is often unfounded because many patients with normal preoperative pulmonary function often require prolonged oxygen supplementation even after minimal resection of lung tissue. Using a murine model of pulmonary resection and peripheral blood samples from patients undergoing resection of the lung or abdominal organs, we demonstrated that lung surgery initiates a proinflammatory loop that results in damage to the remaining lung tissue, noncardiogenic pulmonary edema, hypoxia, and even death. Specifically, we demonstrated that resection of murine lung tissue increased concentrations of the homeostatic cytokine interleukin-7, which led to local and systemic activation of type 2 innate lymphoid cells. This process activated lung-resident eosinophils and facilitated stress-induced eosinophil maturation in the bone marrow in a granulocyte-macrophage colony-stimulating factor–dependent manner, resulting in systemic eosinophilia in both mice and humans. Up-regulation of inducible nitric oxide synthase in lung-resident eosinophils led to tissue nitrosylation, pulmonary edema, hypoxia, and, at times, death. Disrupting this activation cascade at any stage ameliorated deleterious outcomes and improved survival after lung resection in the mouse model. Our data suggest that repurposing US Food and Drug Administration–approved eosinophil-targeting strategies may potentially offer a therapeutic intervention to improve outcomes for patients who require lung resection for benign or malignant etiology. Editor's summary: Respiratory failure frequently occurs after lung resection and may not be fully explained by underlying respiratory disease or the size of the resection. Here, Mei and colleagues used patient samples and mouse models of pneumonectomy to show that lung resection specifically leads to increased percentages of eosinophils through a mechanism involving production of IL-7 by γδ T cells, leading to granulocyte-macrophage colony-stimulating factor production by type 2 innate lymphoid cells, ultimately resulting in increased eosinophil maturation, activation, and production of reactive oxygen species that injure the remaining lung. Targeting different points in this pathway reduced lung damage and improved survival of mice after lung resection, suggesting that perioperative administration of agents that target eosinophils or neutralize nitric oxide synthase could potentially reduce the risk of respiratory failure after lung resection. —Melissa L. Norton [ABSTRACT FROM AUTHOR]

Summary The etiology of allergy is closely linked to type 2 inflammatory responses ultimately leading to the production of allergen‐specific immunoglobulin E (IgE), a key driver of many allergic conditions. At a high level, initial allergen exposure disrupts epithelial integrity, triggering local inflammation via alarmins including IL‐25, IL‐33, and TSLP, which activate type 2 innate lymphoid cells as well as other immune cells to secrete type 2 cytokines IL‐4, IL‐5 and IL‐13, promoting Th2 cell development and eosinophil recruitment. Th2 cell dependent B cell activation promotes the production of allergen‐specific IgE, which stably binds to basophils and mast cells. Rapid degranulation of these cells upon allergen re‐exposure leads to allergic symptoms. Recent advances in our understanding of the molecular and cellular mechanisms underlying allergic pathophysiology have significantly shaped the development of therapeutic intervention strategies. In this review, we highlight key therapeutic targets within the allergic cascade with a particular focus on past, current and future treatment approaches using monoclonal antibodies. Specific targeting of alarmins, type 2 cytokines and IgE has shown varying degrees of clinical benefit in different allergic indications including asthma, chronic spontaneous urticaria, atopic dermatitis, chronic rhinosinusitis with nasal polyps, food allergies and eosinophilic esophagitis. While multiple therapeutic antibodies have been approved for clinical use, scientists are still working on ways to improve on current treatment approaches. Here, we provide context to understand therapeutic targeting strategies and their limitations, discussing both knowledge gaps and promising future directions to enhancing clinical efficacy in allergic disease management. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases that span simple steatosis, metabolic dysfunctionassociated steatohepatitis (MASH) and fibrosis and may progress to cirrhosis and cancer. The pathogenesis of MASLD is multifactorial and is driven by environmental, genetic, metabolic and immune factors. This review will focus on the role of the type 3 cytokines IL-17 and IL-22 in MASLD pathogenesis and progression. IL-17 and IL-22 are produced by similar adaptive and innate immune cells such as Th17 and innate lymphoid cells, respectively. IL-17-related signaling is upregulated during MASLD resulting in increased chemokines and proinflammatory cytokines in the liver microenvironment, enhanced recruitment of myeloid cells and T cells leading to exacerbation of inflammation and liver disease progression. IL-17 may also act directly by activating hepatic stellate cells resulting in increased fibrosis. In contrast, IL-22 is a pleiotropic cytokine with a dominantly protective signature in MASLD and is currently being tested as a therapeutic strategy. IL-22 also exhibits beneficial metabolic effects and abrogates MASH-related inflammation and fibrosis development via inducing the production of anti-oxidants and anti-apoptotic factors. A sex-dependent effect has been attributed to both cytokines, most importantly to IL-22 in MASLD or related conditions. Altogether, IL-17 and IL-22 are key effectors in MASLD pathogenesis and progression. We will review the role of these two cytokines and cells that produce them in the development of MASLD, their interaction with host factors driving MASLD including sexual dimorphism, and their potential therapeutic benefits. [ABSTRACT FROM AUTHOR]

Group 1 innate lymphoid cells (ILCs) comprise conventional natural killer (cNK) cells and type 1 innate lymphoid cells (ILC1s). The main functions of liver cNK cells and ILC1s not only include directly killing target cells but also regulating local immune microenvironment of the liver through the secretion of cytokines. Uncovering the intricate mechanisms by which transcriptional factors regulate and influence the functions of liver cNK cells and ILC1s, particularly within the context of liver tumors, presents a significant opportunity to amplify the effectiveness of immunotherapies against liver malignancies. Using Ncr1-drived conditional knockout mouse model, our study reveals the regulatory role of Prdm1 in shaping the composition and maturation of cNK cells. Although Prdm1 did not affect the killing function of cNK cells in an in vivo cytotoxicity model, a significant increase in cancer metastasis was observed in Prdm1 knockout mice. Interferon-gamma (IFN-γ), granzyme B, and perforin secretion decreased significantly in Prdm1-deficient cNK cells and liver ILC1s. Single-cell RNA sequencing (scRNA-seq) data also provided evidences that Prdm1 maintains functional subsets of cNK cells and liver ILC1s and facilitates communications between cNK cells, liver ILC1s, and macrophages. The present study unveiled a novel regulatory mechanism of Prdm1 in cNK cells and liver ILC1s, showing promising potential for developing innovative immune therapy strategies against liver cancer. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor （HIF） are a family of molecules that are critical for regulating cellular adaptation to hypoxia, which can be activated by hypoxia and other stimuli, and then translocated into nucleus, where they modulate the transcription of target genes. Under the pathological conditions, such as inflammation and tumor, tissue microenvironment is often hypoxic. Innate lymphoid cells （ILCs） and T lymphocytes serve as important effector cells in defense against infection and tumor, and their functions are regulated by HIF proteins. In recent years, increasing evidence highlights the importance of HIF1α and HIF2α, two members of the HIF family, in regulating ILCs and T cells, providing new insights into mechanisms and treatment of diseases. This review summarizes the research progress on the role of HIF family proteins in ILCs and T cells and the underlying mechanisms. [ABSTRACT FROM AUTHOR]

This article discusses the potential therapeutic effects of interferon-lambda (IFN-λ) inhalation on allergic asthma. The study found that inhalation of IFN-λ reduced airway hyperresponsiveness, improved lung histopathology, and suppressed Th2 immune responses in mice with allergic asthma. Additionally, IFN-λ inhalation led to a decrease in the production of interleukin-33 (IL-33) in the respiratory epithelial cells, which is a key cytokine involved in the pathogenesis of allergic asthma. These findings suggest that delivering IFN-λ to the respiratory epithelium could be an effective treatment for allergic asthma. The research was supported by grants from the National Research Foundation of Korea and the Ministry of Health and Welfare of the Republic of Korea. [Extracted from the article]

The innate immune system, composed of neutrophils, basophils, eosinophils, myeloid-derived suppressor cells (MDSCs), macrophages, dendritic cells (DCs), mast cells (MCs), and innate lymphoid cells (ILCs), is the first line of defense. Growing evidence demonstrates the crucial role of innate immunity in tumor initiation and progression. Several studies support the idea that innate immunity, through the release of pro- and/or anti-inflammatory cytokines and tumor growth factors, plays a significant role in the pathogenesis, progression, and prognosis of cutaneous malignant melanoma (MM). Cutaneous melanoma is the most common skin cancer, with an incidence that rapidly increased in recent decades. Melanoma is a highly immunogenic tumor, due to its high mutational burden. The metastatic form retains a high mortality. The advent of immunotherapy revolutionized the therapeutic approach to this tumor and significantly ameliorated the patients' clinical outcome. In this review, we will recapitulate the multiple roles of innate immune cells in melanoma and the related implications for immunotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Prostaglandin D2 (PGD2), which is produced mainly by Th2 cells and mast cells, promotes a type-2 immune response by activating Th2 cells, mast cells, eosinophils, and group 2 innate lymphoid cells (ILC2s) via its receptor, chemoattractant receptor-homologous molecules on Th2 cells (CRTH2). However, the role of CRTH2 in models of airway inflammation induced by sensitization without adjuvants, in which both IgE and mast cells may play major roles, remain unclear. Methods: Wild-type (WT) and CRTH2-knockout (KO) mice were sensitized with ovalbumin (OVA) without an adjuvant and then challenged intranasally with OVA. Airway inflammation was assessed based on airway hyperresponsiveness (AHR), lung histology, number of leukocytes, and levels of type-2 cytokines in the bronchoalveolar lavage fluid (BALF). Results: AHR was significantly reduced after OVA challenge in CRTH2 KO mice compared to WT mice. The number of eosinophils, levels of type-2 cytokines (IL-4, IL-5, and IL-13) in BALF, and IgE concentration in serum were decreased in CRTH2 KO mice compared to WT mice. However, lung histological changes were comparable between WT and CRTH2 KO mice. Conclusion: CRTH2 is responsible for the development of asthma responses in a mouse model of airway inflammation that features prominent involvement of both IgE and mast cells. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the development of steroid resistance in asthma remain unclear. To establish whether as well as the mechanisms by which the activation of Janus kinases (JAKs) is involved in the development of steroid resistance in asthma, murine steroid‐resistant models of the proliferation of group 2 innate lymphoid cells (ILC2s) in vitro and asthmatic airway inflammation in vivo were analysed. ILC2s in the lungs of BALB/c mice were sorted and then incubated with IL‐33, thymic stromal lymphopoietin (TSLP), and/or IL‐7 with or without dexamethasone (10 nM), the pan‐JAK inhibitor, delgocitinib (1–10 000 nM), and/or the Bcl‐xL inhibitor, navitoclax (1–100 nM), followed by the detection of viable and apoptotic cells. The anti‐apoptotic factor, Bcl‐xL was detected in ILC2s by flow cytometry. As a steroid‐resistant asthma model, ovalbumin (OVA)‐sensitized BALB/c mice were intratracheally challenged with OVA at a high dose of 500 μg four times. Dexamethasone (1 mg/kg, i.p.), delgocitinib (3–30 mg/kg, p.o.), or navitoclax (30 mg/kg, p.o.) was administered during the challenges. Cellular infiltration into the lungs was analysed by flow cytometry. Airway remodelling was histologically evaluated. The following results were obtained. (1) Cell proliferation concomitant with a decrease in apoptotic cells was induced when ILC2s were cultured with TSLP and/or IL‐7, and was potently inhibited by dexamethasone. In contrast, when the culture with TSLP and IL‐7 was performed in the presence of IL‐33, the proliferative response exhibited steroid resistance. Steroid‐resistant ILC2 proliferation was suppressed by delgocitinib in a concentration‐dependent manner. (2) The culture with IL‐33, TSLP, and IL‐7 induced the overexpression of Bcl‐xL, which was clearly inhibited by delgocitinib, but not by dexamethasone. When ILC2s were treated with navitoclax, insensitivity to dexamethasone was significantly cancelled. (3) The development of airway remodelling and the infiltration of ILC2s into the lungs in the asthma model were not suppressed by dexamethasone, but were dose‐dependently inhibited by delgocitinib. Combination treatment with dexamethasone and either delgocitinib or navitoclax synergistically suppressed these responses. Therefore, JAKs appear to play significant roles in the induction of steroid resistance by up‐regulating Bcl‐xL in ILC2s. The inhibition of JAKs and Bcl‐xL has potential as pharmacotherapy for steroid‐resistant asthma, particularly that mediated by ILC2s. [ABSTRACT FROM AUTHOR]

In maintaining organismal homeostasis, gut immunity plays a crucial role. The coordination between the microbiota and the immune system through bidirectional interactions regulates the impact of microorganisms on the host. Our research focused on understanding the relationships between substantial changes in jejunal intestinal flora and metabolites and intestinal immunity during porcine epidemic diarrhea virus (PEDV) infection in piglets. We discovered that Lactobacillus rhamnosus GG (LGG) could effectively prevent PEDV infection in piglets. Further investigation revealed that LGG metabolites interact with type 3 innate lymphoid cells (ILC3s) in the jejunum of piglets through the aryl hydrocarbon receptor (AhR). This interaction promotes the activation of ILC3s and the production of interleukin-22 (IL-22). Subsequently, IL-22 facilitates the proliferation of IPEC-J2 cells and activates the STAT3 signaling pathway, thereby preventing PEDV infection. Moreover, the AhR receptor influences various cell types within organoids, including intestinal stem cells (ISCs), Paneth cells, and enterocytes, to promote their growth and development, suggesting that AhR has a broad impact on intestinal health. In conclusion, our study demonstrated the ability of LGG to modulate intestinal immunity and effectively prevent PEDV infection in piglets. These findings highlight the potential application of LGG as a preventive measure against viral infections in livestock. IMPORTANCE We observed high expression of the AhR receptor on pig and human ILC3s, although its expression was negligible in mouse ILC3s. ILC3s are closely related to the gut microbiota, particularly the secretion of IL-22 stimulated by microbial signals, which plays a crucial regulatory role in intestinal immunity. In our study, we found that metabolites produced by beneficial gut bacteria interact with ILC3s through AhR, thereby maintaining intestinal immune homeostasis in pigs. Moreover, LGG feeding can enhance the activation of ILC3s and promote IL-22 secretion in the intestines of piglets, ultimately preventing PEDV infection. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic skin inflammation influenced by dysregulated skin microbiota, with the role of microbiota in psoriasis gaining increasing prominence. Bacterial extracellular vesicles (bEVs) serve as crucial regulators in the interaction between hosts and microbiota. However, the mechanism underlying the therapeutic potential of bEVs from commensal bacteria in psoriasis remains unclear. Here, we investigated the therapeutic role of Cutibacterium acnes (C. acnes)-derived extracellular vesicles (CA-EVs) in psoriasis treatment. To prolong the active duration of CA-EVs, we encapsulated them in gelatin methacrylate (GelMA) to fabricate hydrogel microspheres (CA-EVs@GHM) with sustained release properties. As GelMA degraded, CA-EVs were gradually released, maintaining a high concentration in mouse skin even 96 h post-treatment. In human keratinocyte cells (HaCaT), CA-EVs@GHM enhanced resistance to Staphylococcus aureus (S. aureus), promoted proliferation and migration of HaCaT cells exposed to S. aureus , and significantly reduced the expression of inflammatory genes such as interleukin (IL)-6 and C-X-C motif chemokine ligand 8 (CXCL8). In vivo , CA-EVs@GHM, more potent than CA-EVs alone, markedly attenuated proinflammatory gene expression, including tumor necrosis factor (TNF), Il6, Il17a, Il22 and Il23a in imiquimod (IMQ)-induced psoriasis-like mice, and restored skin barrier function. 16S rRNA sequencing revealed that CA-EVs@GHM might provide therapeutic effects against psoriasis by restoring microbiota diversity on the back skin of mice, reducing Staphylococcus colonization, and augmenting lipid metabolism. Furthermore, flow cytometry analysis showed that CA-EVs@GHM prevented the conversion of type 2 innate lymphoid cells (ILC2) to type 3 innate lymphoid cells (ILC3) in psoriasis-like mouse skin, reducing the pathogenic ILC3 population and suppressing the secretion of IL-17 and IL-22. In summary, our findings demonstrate that the long-term sustained release of CA-EVs alleviated psoriasis symptoms by controlling the transformation of innate lymphoid cells (ILCs) subgroups and restoring skin microbiota homeostasis, thus offering a promising therapy for psoriasis treatment. Cutibacterium acnes , which is reduced in psoriasis skin, has been reported to promote skin homeostasis by regulating immune balance. Compared to live bacteria, bacterial extracellular vesicles (bEVs) are less prone to toxicity and safety concerns. bEVs play a pivotal role in maintaining bacterial homeostasis and modulating the immune system. However,bEVs without sustained release materials are unable to function continuously in chronic diseases. Therefore, we utilized hydrogel microspheres to encapsulate Cutibacterium acnes (C. acnes)-derived extracellular vesicles (CA-EVs), enabling long term sustained release. Our findings indicate that, CA-EVs loaded gelatin methacrylate hydrogel microspheres (CA-EVs@GHM) showed superior therapeutic effects in treating psoriasis compared to CA-EVs. CA-EVs@GHM exhibited a more significant regulation of pathological type 3 innate lymphoid cells (ILC3) and skin microbiota, providing a promising approach for microbiota-derived extracellular vesicle therapy in the treatment of skin inflammation. [Display omitted] [ABSTRACT FROM AUTHOR]

How group 3 innate lymphoid cells (ILC3s) regulate mucosal protection in the presence of T cells remains poorly understood. Here, we examined ILC3 function in intestinal immunity using ILC3-deficient mice that maintain endogenous T cells, T helper 17 (TH17) cells, and secondary lymphoid organs. ILC3s were dispensable for generation of TH17 and TH22 cell responses to commensal and pathogenic bacteria, and absence of ILC3s did not affect IL-22 production by CD4 T cells before or during infection. However, despite the presence of IL-22–producing T cells, ILC3s and ILC3-derived IL-22 were required for maintaining homeostatic functions of the intestinal epithelium. T cell–sufficient, ILC3-deficient mice were capable of pathogen clearance and survived infection with a low dose of Citrobacter rodentium. However, ILC3s promoted pathogen tolerance at early time points of infection by activating tissue-protective immune pathways. Consequently, ILC3s were indispensable for survival after high-dose infection. Our results demonstrate a context-dependent role for ILC3s in immune-sufficient animals and provide a blueprint for uncoupling of ILC3 and TH17 cell functions. Editor's summary: Group 3 innate lymphoid cells (ILC3s) contribute to intestinal homeostasis and immunity against gut pathogens. Distinguishing the functions of ILC3s from those of T helper 17 (TH17) cells has remained challenging because of similar transcription factor dependencies and cytokine production profiles. To better define ILC3-specific roles, Araujo et al. developed genetically engineered mice that lack ILC3s while retaining endogenous T cells and secondary lymphoid organs. ILC3s were the primary producers of IL-22, which was required for the maintenance of intestinal epithelial cell homeostasis. Whereas TH17 cells were sufficient to protect against low-dose Citrobacter rodentium infection, ILC3s provided early protection and were required for survival after high-dose infection. Together, these findings identify nonredundant functions of ILC3s in mucosal homeostasis and immunity. —Claire Olingy [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) implies different conditions where insulin resistance constitutes a major hallmark of the disease. The disease incurs a high risk for the development of cardiovascular complications, and takes its toll in regard to the gut–liver axis (pancreas, primary liver and colorectal)-associated immunity. The modulation of immunometabolic responses by immunonutritional factors (IFs) has emerged as a key determinant of the gut–liver axis' metabolic and immune health. IFs from plant seeds have shown in vitro and pre-clinical effectiveness primarily in dealing with various immunometabolic and inflammatory diseases. Only recently have immunonutritional studies established the engagement of innate intestinal immunity to effectively control immune alterations in inflamed livers preceding the major features of the MetS. However, integrative analyses and the demonstration of causality between IFs and specific gut–liver axis-associated immunometabolic imbalances for the MetS remain ill-defined in the field. Herein, a better understanding of the IFs with a significant role in the MetS, as well as within the dynamic interplay in the functional differentiation of innate immune key effectors (i.e., monocytes/macrophages), worsening or improving the disease, could be of crucial relevance. The development of an adequate intermediary phenotype of these cells can significantly contribute to maintaining the function of Tregs and innate lymphoid cells for the prevention and treatment of MetS and associated comorbidities. [ABSTRACT FROM AUTHOR]

Group 3 innate lymphoid cells (ILC3s) play key roles in intestinal inflammation. Olfactomedin 4 (OLFM4) is highly expressed in the colon and has a potential role in dextran sodium sulfate-induced colitis. However, the detailed mechanisms underlying the effects of OLFM4 on ILC3-mediated colitis remain unclear. In this study, we identify OLFM4 as a positive regulator of IL-22+ILC3. OLFM4 expression in colonic ILC3s increases substantially during intestinal inflammation in humans and mice. Compared to littermate controls, OLFM4-deficient (OLFM4−/−) mice are more susceptible to bacterial infection and display greater resistance to anti-CD40 induced innate colitis, together with impaired IL-22 production by ILC3, and ILC3s from OLFM4−/−mice are defective in pathogen resistance. Besides, mice with OLFM4 deficiency in the RORγt compartment exhibit the same trend as in OLFM4−/−mice, including colonic inflammation and IL-22 production. Mechanistically, the decrease in IL-22+ILC3 caused by OLFM4 deficiency involves the apoptosis signal-regulating kinase 1 (ASK1)- p38 MAPK signaling-dependent downregulation of RAR-related orphan receptor gamma (RORγt) protein. The OLFM4-metadherin (MTDH) complex upregulates p38/RORγt signaling, which is necessary for IL-22+ILC3 activation. The findings indicate that OLFM4 is a novel regulator of IL-22+ILC3 and essential for modulating intestinal inflammation and tissue homeostasis. The modulation of ASK1-p38/RORγt signaling by OLFM4 suggests a novel mechanism in the regulation of ILC3-mediated gut inflammation, providing valuable insights for potential therapeutic interventions. [ABSTRACT FROM AUTHOR]

Increased production of Prostaglandin D2 (PGD2) is linked to development and progression of asthma and allergy. PGD2 is rapidly degraded to its metabolites, which initiate type 2 innate lymphoid cells (ILC2) migration and IL-5/IL-13 cytokine secretion in a PGD2 receptor 2 (DP2)-dependent manner. Blockade of DP2 has shown therapeutic benefit in subsets of asthma patients. Cellular mechanisms of ILC2 activity in response to PGD2 and its metabolites are still unclear. We hypothesized that ILC2 respond non-uniformly to PGD2 metabolites. ILC2s were isolated from peripheral blood of patients with atopic asthma. ILC2s were stimulated with PGD2 and four PGD2 metabolites (Δ12-PGJ2, Δ12-PGD2, 15-deoxyΔ12,14-PGD2, 9α,11β-PGF2) with or without the selective DP2 antagonist fevipiprant. Total RNA was sequenced, and differentially expressed genes (DEG) were identified by DeSeq2. Differential gene expression analysis revealed an upregulation of pro-inflammatory DEGs in ILC2s stimulated with PGD2 (14 DEGs), Δ12-PGD2 (27 DEGs), 15-deoxyΔ12,14-PGD2 (56 DEGs) and Δ12-PGJ2 (136 DEGs), but not with 9α,11β-PGF2. Common upregulated DEGs were i.e. ARG2, SLC43A2, LAYN, IGFLR1, or EPHX2. Inhibition of DP2 via fevipiprant mainly resulted in downregulation of pro-inflammatory genes such as DUSP4, SPRED2, DUSP6, ETV1, ASB2, CD38, ADGRG1, DDIT4, TRPM2, or CD69. DEGs were related to migration and various immune response-relevant pathways such as "chemokine (C-C motif) ligand 4 production", "cell migration", "interleukin-13 production", "regulation of receptor signaling pathway via JAK-STAT", or "lymphocyte apoptotic process", underlining the pro-inflammatory effects of PGD2 metabolite-induced immune responses in ILC2s as well as the anti-inflammatory effects of DP2 inhibition via fevipiprant. Furthermore, PGD2 and metabolites showed distinct profiles in ILC2 activation. Overall, these results expand our understanding of DP2 initiated ILC2 activity. [ABSTRACT FROM AUTHOR]

Hantaviruses cause the acute zoonotic diseases hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Infected patients show strong systemic inflammation and immune cell activation. NK cells are highly activated in HFRS, suggesting that also other innate lymphoid cells (ILCs) might be responding to infection. Here, we characterized peripheral ILC responses, and measured plasma levels of soluble factors and plasma viral load, in 17 Puumala virus (PUUV)-infected HFRS patients. This revealed an increased frequency of ILC2 in patients, in particular the ILC2 lineage-committed c-Kitlo ILC2 subset. Patients' ILCs showed an activated profile with increased proliferation and displayed altered expression of several homing markers. How ILCs are activated during viral infection is largely unknown. When analyzing PUUV-mediated activation of ILCs in vitro we observed that this was dependent on type I interferons, suggesting a role for type I interferons—produced in response to virus infection–in the activation of ILCs. Further, stimulation of naïve ILC2s with IFN-β affected ILC2 cytokine responses in vitro, causing decreased IL-5 and IL-13, and increased IL-10, CXCL10, and GM-CSF secretion. These results show that ILCs are activated in HFRS patients and suggest that the classical antiviral type I IFNs are involved in shaping ILC functions. Author summary: Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) are acute zoonotic diseases caused by orthohantaviruses. Hantavirus initially infect the lung and then spread systemically, primarily infecting endothelial cells. The innate lymphoid cell (ILC) family consists of ILC1, ILC2, ILC3, and natural killer (NK) cells. While NK cells are well studied in viral infections, less is known regarding the other ILCs. Hantavirus-infected patients show highly activated immune cells, including NK cells, indicating that also other innate lymphoid cells (ILCs) might be affected. We discovered that Puumala virus (PUUV)-infected HFRS patients show increased frequency of ILC2s in circulation, and that ILCs are activated with an altered homing receptor expression pattern. Little is known regarding how ILCs are activated during viral infection. When analyzing, in vitro, for mechanisms behind activation we observed a PUUV-induced type I IFN-dependent activation of ILCs and that IFN-β affects ILC2 cytokine responses. These findings suggest that ILC functions are affected by classical antiviral type I IFNs. [ABSTRACT FROM AUTHOR]

Introduction: Innate lymphoid cells (ILCs) are enriched at mucosal surfaces where they respond rapidly to environmental stimuli and contribute to both tissue inflammation and healing. Methods: To gain insight into the role of ILCs in the pathology and recovery from COVID-19 infection, we employed a multi-omics approach consisting of Abseq and targeted mRNA sequencing to respectively probe the surface marker expression, transcriptional profile and heterogeneity of ILCs in peripheral blood of patients with COVID-19 compared with healthy controls. Results: We found that the frequency of ILC1 and ILC2 cells was significantly increased in COVID-19 patients. Moreover, all ILC subsets displayed a significantly higher frequency of CD69-expressing cells, indicating a heightened state of activation. ILC2s from COVID-19 patients had the highest number of significantly differentially expressed (DE) genes. The most notable genes DE in COVID-19 vs healthy participants included a) genes associated with responses to virus infections and b) genes that support ILC self-proliferation, activation and homeostasis. In addition, differential gene regulatory network analysis revealed ILC-specific regulons and their interactions driving the differential gene expression in each ILC. Discussion: Overall, this study provides mechanistic insights into the characteristics of ILC subsets activated during COVID-19 infection. [ABSTRACT FROM AUTHOR]

Background: The periodontal ligament (PDL) experiences considerable mechanical stresses between teeth and bone, vital for tissue adaptation, especially in orthodontic tooth movement (OTM). While recent research emphasizes the role of innate lymphoid cells (ILCs) in regulating sterile inflammation, their involvement in periodontal tissues during OTM remains largely unexplored. Methods: In this study, PDL tissues from orthodontic patients (n = 8) were examined using flow cytometry to detect ILC subtypes. Transwell co-culture systems were used to expose PDL cells to mechanical strain, followed by measuring migration and ratios of sorted ILC subtypes. Statistical analyses were conducted using paired Student's t-test, Kruskal-Wallis test, Dunn's posttest and one-way/two-way ANOVA with Tukey's post-test (p= 0.05; **, p= 0.01; ***, p= 0.001). Results: Our findings demonstrate a significant increase in CD127+ CD161+ ILC frequencies in PDL tissues during OTM, indicating ILC involvement in sterile inflammation induced by orthodontic forces. Co-culture assays show directed migration of ILC subsets towards PDL cells and substantial proliferation and expansion of ILCs. Conclusions: This study is the first to comprehensively investigate the role of ILCs in sterile inflammation during OTM, revealing their presence and distribution within PDL tissues' innate immune response in vivo, and exploring their migratory and proliferative behavior in vitro. The results suggest a crosstalk between ILCs and PDL cells, potentially influencing the inflammatory response and tissue remodeling processes associated with OTM. [ABSTRACT FROM AUTHOR]