Search Results (46)

(1) Background: Innate lymphoid cells (ILCs) are potent cytokine producers that regulate local immune responses in tissues. Natural killer (NK) cells belong to group 1 ILCs and play an important role in tumor clearance and defense against intracellular pathogens. ILC2 and 3 have been implied in allergic responses and other chronic inflammatory diseases. The role of these cells in the pathogenesis of chronic rhinosinusitis (CRS) is not completely understood. There are changes in the cellular infiltrate in the mucosa of patients with CRS with and without polyps. The aim of this study was to characterize the number and phenotype of NK cells, ILC2s and ILC3s in patients with CRS. (2) Methods: Tissue samples were collected from patients with CRS with and without nasal polyps who were undergoing nasal sinus surgery as well as control patients who were undergoing surgery due to non-inflammatory reasons. Lymphocytes were isolated from the tissues using mechanical and enzymatic dissociation. Peripheral blood lymphocytes were obtained from the same patients. All cells were examined by multicolor flow cytometry. NK cells were analyzed for the distribution of CD56^dimCD16⁺ and CD56^brightCD16⁻ subsets and the expression of IL18Rα, CD16, CD57, GATA3, TCF1 and NKp44. In ILC2s, GATA3 and IL18Rα expression was determined, and ILC3s as well as NKp44⁺ and NKp44⁻ILC3 subsets were analyzed for the expression of IL18Rα. (3) Results: There were significantly fewer NK cells in the nasal polyps compared to the peripheral blood of patients with CRSwNP and tissues from CRSsNP patients, which both showed higher levels of TCF1 expression. Irrespective of the disease condition, NK cells in tissues showed lower CD16 expression and a lower frequency of the CD56^dimCD16⁺ subset compared to the peripheral blood mononuclear cells. Additionally, a smaller percentage of NK cells were terminally matured, as measured by CD16⁺ and CD57⁺ expression, in all examined nasal mucosa tissues. In the tissue ILC3s, we predominantly found cells from the NKp44⁻ subset in all groups. ILC3s from CRSsNP patients showed the highest frequencies of IL18Rα⁺ cells of all examined tissues. ILC2s from the polyps ofCRSwNP patients showed higher levels of GATA3 expression than their peripheral blood counterparts. (4) Conclusions: We found that tissue-resident NK cells in mucosa from the nose and sinuses are a more heterogenous and less mature population than those in peripheral blood. Expression of the examined markers in NK cells was similar among groups. NK cell frequency, both in blood and tissue from CRSsNP patients, was higher than in the other groups, indicating that these cells might play an important role in this phenotype. Changes in the IL18Rα expression of ILC3s suggest a potential role of IL18 signaling in CRS pathogenesis. Full article

Group 2 innate lymphoid cells (ILC2s) are tissue-resident immune cells that play a central role in type 2 immunity. Beyond cytokine signaling, they integrate inputs from lipids, nutrients, neuroendocrine mediators, and local metabolic cues, establishing cellular metabolism as a key regulator of their function. Immunometabolism provides a framework to understand how ILC2s adapt to diverse tissue environments such as the lung, adipose tissue, gut, skin, and brain, each defined by distinct nutrient availability, oxygen tension, and inflammatory conditions. Unlike many immune cells that primarily rely on glycolysis, ILC2s dynamically balance glycolysis, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS) depending on activation state and tissue context. Lipids not only serve as energy substrates but also regulate membrane organization, lipid raft–dependent signaling, and the generation of bioactive mediators, including eicosanoids, oxysterols, and sphingolipids. Emerging evidence linking cholesterol biosynthesis, steroid metabolism, and sphingolipid signaling to ILC2 function underscores the importance of lipid-dependent immune regulation. Dysregulation of these pathways contributes to chronic inflammatory diseases such as asthma, metabolic disorders, and fibrosis. Targeting metabolic pathways and checkpoints may therefore offer new strategies to modulate ILC2-driven pathology. This review summarizes current insights into metabolic programs governing ILC2 activation, survival, and plasticity and highlights emerging therapeutic opportunities. Full article

Helminths infect a quarter of the human population and are controlled in the frame of a canonical type-2 immune response. Interleukin-9 is a cytokine with pleiotropic functions during type-2 immunity that can be produced by many different cells. Accumulating evidence suggest that IL-9 is of particular relevance in controlling intestinal helminth infections. Using mice infected with the parasitic nematode Strongyloides ratti, we showed previously that ejection from the intestine depends on IL-9 and IL-9-mediated activation of mucosal mast cells. Here we use IL-9 reporter mice to identify the relevant cellular sources of IL-9 in vivo. We report that predominantly CD4⁺ T cells and group 2 innate lymphoid cells (ILC2s) produced IL-9 in S. ratti-infected or IL-33-treated mice. Interestingly, the IL-33-mediated induction of IL-9 and subsequent mast cell degranulation was modulated by concurrent S. ratti infection. While the IL-33-mediated expansion of IL-9-producing ILC2s was supressed by S. ratti infection, IL-9-producing CD4⁺ T cells were proportionally increased. Finally, we show that S. ratti-derived E/S products interfered with IL-9 production by BM-derived ILC2 in vitro. In conclusion, we have identified that ILC2 and CD4⁺ T cells produce IL-9 during S. ratti infection, and that ILC2 responses are suppressed by S. ratti products. Full article

Background/Objectives: Breast cancer is the most common cancer in women. The neutrophil/lymphocyte ratio (NLR) is an emerging biomarker from peripheral blood that has been associated with breast cancer prognosis in some studies; however, some studies fail to demonstrate an association. We stratified breast cancer patients into invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) cohorts to evaluate if any meaningful association could be found in either cohort between NLR and mortality. Additionally, no prior studies have examined the relationship between NLR and background parenchymal enhancement (BPE) on breast MRI, an imaging feature linked to increased breast cancer risk and a potential imaging prognostic biomarker, so we examined the relationship between BPE and NLR in the two cohorts. Methods: This retrospective study included 794 breast cancer patients who had either IDC or ILC. Radiologists’ MRI reports and their BI-RADS categorization of BPE (1 = minimal, 2 = mild, 3 = moderate, 4 = marked) were extracted and recorded. The NLR was calculated from blood counts obtained prior to treatment. Tumor characteristics were also recorded. Results: For patients with ILC, NLR was found to be associated with mortality. Additionally, patients with ILC and a high BPE had a significantly higher mean NLR compared to all other groups, including low BPE groups and all IDC groups. Conclusions: There is potential value in using NLR, a readily available blood biomarker, in models predicting prognosis in ILC patients. Full article

The concept of united airway disease (UAD) highlights the bidirectional relationship between inflammatory disorders of the upper airways—such as allergic rhinitis and chronic rhinosinusitis with or without nasal polyps (CRSwNP/CRSsNP)—and lower airway diseases, most notably asthma. This paradigm is supported by epidemiological, embryological, and immunological evidence demonstrating that airway inflammation represents a single, interconnected process rather than isolated compartmental pathology. Central to many UAD phenotypes is type 2 (T2) inflammation, driven by cytokines including IL-4, IL-5, and IL-13, and mediated by effector cells such as eosinophils and group 2 innate lymphoid cells (ILC2s). Epithelial barrier dysfunction often serves as the initiating trigger for this shared inflammatory cascade by production of TSLP, IL-25 and IL-33. Optimal diagnosis and management of UAD require an integrated, multidisciplinary framework. Clinical evaluation remains essential for patient characterization but must be complemented by pheno-endotypic assessment using imaging (CT), allergy testing, biomarker profiling (FeNO, blood eosinophils, IgE), and pulmonary function testing (spirometry, impulse oscillometry). Therapeutic strategies are layered, targeting both symptom control and inflammation across airway compartments. Standard approaches include intranasal and inhaled corticosteroids as well as saline irrigations, while severe T2-high disease increasingly benefits from biologic therapies (anti-IL-5/IL-5R, anti-IL-4R, anti-TSLP), which reduce dependence on systemic corticosteroids and surgical interventions such as endoscopic sinus surgery (ESS). Emerging precision-medicine models, particularly the “treatable traits” approach, further underscore the need to view the airway as a unified system. Collectively, these insights reinforce the clinical imperative of addressing upper and lower airway disease as a continuum, ensuring that inflammation in one district is neither overlooked nor treated in isolation. Full article

Der p 23 induces a high-frequency sensitization in allergic individuals. However, its allergenic activity and clinical impact are scarce. We aimed to evaluate the ability of rDer p 23 to induce allergic inflammation in a mouse model and to test IgE reactivity in humans. Female Balb/c mice were sensitized and challenged with rDer p 23 and Dermatophagoides pteronyssinus extract. Specific antibodies were determined by ELISA, inflammatory cell infiltration and goblet cells hyperplasia were evaluated by lung histology, and bronchial hyperreactivity (BHR) was assessed by the FinePoint RC System^TM and whole-body plethysmography (WBP). IgE reactivity was evaluated by ELISA, the basophils activation test (BAT) and the skin pick test (SPT) in humans. rDer p 23, produced in Escherichia coli, adopts a random coil structure, predominantly exists in a monomeric state, and exhibits high stability. rDer p 23-treated mice showed a significant increase in lung resistance and bronchial hyperreactivity, as well as in eosinophils, neutrophils, and T cell count in bronchoalveolar lavage fluid (BALF). Cytokine and antibodies profiles were biased to a Type-2 response. No significant difference was observed in group 2 Innate Lymphoid Cells (ILC-2s) in lung and regulatory T cells (Treg) in the spleen. In asthmatic individuals sensitized to D. pteronyssinus, serum IgE reactivity to rDer p 23 was 67.5%. BAT and SPT results were significantly higher in allergic patients. Our findings support the pro-allergenic role of rDer p 23 in the development of the pathological features of asthma. Full article

Mouse models serve as a means of examining immune changes when genes of interest are knocked out (KO). One group of immune gene-producing cells that have been identified is type 2 innate lymphoid cells (Ilc2). These cells are involved in the production of Th2 equivalent immune responses and signal cytokine production during the resolution of Nippostrongylus brasiliensis parasite infection in mice lungs. However, many questions about Ilc2 activity in the gut remain. To study this, retinoic acid receptor (RAR)-related orphan receptor alpha (RORα)-deficient mice were infected with adult N. brasiliensis and arranged into four treatment groups. Ten days post-infection (dpi), mouse ileum tissue was extracted for RNA-Seq. The RORα-deficient mice showed little change in gene expression at 10 dpi (N = 51) when compared to the WT mice at 10 dpi (N = 915), displaying dysregulation within the mouse gut. Based on the results, the gene expression in the gut of Ilc2-deficient mice denoted that the inability to craft Ilc2 cells left the mice unable to mount classical helminth immune responses involving humoral, mast cell, and antibody Th2-driven reactions. Overall, the results showed the importance of Ilc2 in the gut during N. brasiliensis infections and the effect that the lack of these cells had on immunity. Full article

Purpose: Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the most common breast cancer types. While they differ biologically and pathologically, their association with axillary lymph node (ALN) metastasis and survival remains unclear. This study compares the clinical features of ILC and IDC to evaluate ALN surgery considerations for ILC patients. Materials and Methods: We retrospectively analyzed 3543 patients who underwent upfront surgery for early breast cancer at Yonsei University Severance Hospital between January 2015 and December 2019. Multivariate logistic regression assessed factors linked to ALN metastasis, while Cox regression identified predictors of recurrence and survival. Results: Among the patients, 92.1% had IDC and 7.9% had ILC. T2-stage tumors were more prevalent in ILC (31.4% vs. 18.1%, p < 0.001). The rates of ALN metastasis were similar between the groups (IDC: 21.1%, ILC: 24.6%, p = 0.655); however, the presence of more than two metastatic ALNs was more frequent in ILC (9.6% vs. 5.0%, p = 0.004). Factors associated with having >2 metastatic ALNs included histology, suspicious axillary ultrasound, T stage, and lymphovascular invasion. The median follow-up period was 65 months, with no significant differences observed in 8-year recurrence-free survival (ILC: 95.2%, IDC: 94.1%, p = 0.134) or 5-year overall survival (ILC: 97.1%, IDC: 97.4%, p = 0.289). Conclusions: ILC features larger tumors and a higher nodal burden but has similar survival rates to IDC with proper treatment. Caution is essential in axillary surgery to avoid underestimating the nodal burden. Full article

Background: Growing evidence attests to the multifaceted roles of group 2 innate lymphoid cells (ILC2s) in cancer immunity. They exhibit either pro- or anticancer activity depending on tumor type but their function in Multiple Myeloma (MM) is still not elucidated. Methods: The bone marrow (BM) and peripheral blood (PB) of patients (pts) with MM or precancerous conditions were collected, and specific properties of ILC2 subsets were assessed by flow cytometry. Results: By dissecting ILC2s according to c-Kit marker, we observed that NKp30 and NKG2D were mainly confined to c-Kit^hi ILC2s, while levels of DNAM-1 was significantly higher in fully mature c-Kit^lo cells. Among the total MM-associated ILC2s (MM-ILC2s), we observed a significant increase in c-the Kit^lo subset, but the expression of DNAM-1 in these cells was significantly reduced, especially in BM. Interestingly, MM-ILC2s from PB expressed granzyme B (GZMB), but its expression was impaired in BM-ILC2s. Accordingly, MM cells were susceptible to killing by MM-ILC2s derived from PB while eluding ILC2 surveillance in BM. Indeed, in MM-ILC2s derived from BM, the downregulation of DNAM-1 is accompanied by the upregulation of TIGIT, which mediate cell death in ILC2s upon recognition of the cognate ligands expressed by MM cells. These ILC2 changes appeared in clinical precursor conditions and eventually accumulated with disease progression. Conclusions: MM-ILC2s can act as cytolytic immune effectors that are fully competent in PB. However, MM cells shift ILC2 fate towards cell death in BM via the upregulation of TIGIT, thereby representing a potential therapeutic target to restore ILC2 antitumor activity. Full article

In patients with aspirin-exacerbated respiratory disease (AERD), there is disparate regulation of prostaglandin E2 (PGE₂) and prostaglandin D₂ (PGD₂). Both prostanoids are synthesised by cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). However, while the basal synthesis of PGE₂ tends to decrease, that of PGD₂ increases in patients with AERD. Furthermore, both behave differently in response to the inhibitory action of NSAIDs on COX-1: PGE₂ levels decrease while PGD₂ increases. Increased PGD₂ release correlates with nasal, bronchial, and extra-pulmonary symptoms caused by aspirin in AERD. The proposed hypothesis establishes that the answer to this paradoxical dissociation can be found in the airway epithelium. This is based on the observation that reduced COX-2 mRNA and/or protein expression is associated with reduced PGE₂ synthesis in cultured fibroblast and epithelial cells from AERD compared to patients with asthma who are aspirin-tolerant and healthy subjects. The low production of PGE₂ by the airway epithelium in AERD results in an excessive release of alarmins (TSLP, IL-33), which in turn contributes to activating group 2 innate lymphoid cells (ILC2s) and PGD₂ synthesis by mast cells and eosinophils. Aspirin, by further increasing the diminished PGE₂ regulation capacity in AERD, leads to respiratory reactions associated with the surge in PGD₂ from mast cells and eosinophils. In summary, the downregulation of COX-2 and the subsequent low production of PGE₂ by airway cells account for the apparently paradoxical increased production of PGD₂ by mast cells and eosinophils at the baseline and after aspirin provocation in patients with AERD. A better understanding of the role of the airway epithelium would contribute to elucidating the mechanism of AERD. Full article

Asthma is a chronic respiratory condition predominantly driven by a type 2 immune response. Epithelial-derived alarmins such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 orchestrate the activation of downstream Th2 cells and group 2 innate lymphoid cells (ILC2s), along with other immune effector cells. While these alarmins are produced in response to inhaled triggers, such as allergens, respiratory pathogens or particulate matter, disproportionate alarmin production by airway epithelial cells can lead to asthma exacerbations. With alarmins produced upstream of the type 2 inflammatory cascade, understanding the pathways by which these alarmins are regulated and expressed is critical to further explore new therapeutics for the treatment of asthmatic patients. This review emphasizes the critical role of airway epithelium and epithelial-derived alarmins in asthma pathogenesis and highlights the potential of targeting alarmins as a promising therapeutic to improve outcomes for asthma patients. Full article

Cutaneous wounds, both acute and chronic, begin with loss of the integrity, and thus barrier function, of the skin. Surgery and trauma produce acute wounds. There are 22 million surgical procedures per year in the United States alone, based on data from the American College of Surgeons, resulting in a prevalence of 6.67%. Acute traumatic wounds requiring repair total 8 million per year, 2.42% or 24.2 per 1000. The cost of wound care is increasing; it approached USD 100 billion for just Medicare in 2018. This burden for wound care will continue to rise with population aging, the increase in metabolic syndrome, and more elective surgeries. To heal a wound, an orchestrated, evolutionarily conserved, and complex series of events involving cellular and molecular agents at the local and systemic levels are necessary. The principal factors of this important function include elements from the neurological, cardiovascular, immune, nutritional, and endocrine systems. The objectives of this review are to provide clinicians engaged in wound care and basic science researchers interested in wound healing with an updated synopsis from recent publications. We also present data from our primary investigations, testing the hypothesis that cannabidiol can alter cutaneous wound healing and documenting their effects in wild type (C57/BL6) and db/db mice (Type 2 Diabetes Mellitus, T2DM). The focus is on the potential roles of the endocannabinoid system, cannabidiol, and the important immune-regulatory wound cytokine IL-33, a member of the IL-1 family, and connective tissue growth factor, CTGF, due to their roles in both normal and abnormal wound healing. We found an initial delay in the rate of wound closure in B6 mice with CBD, but this difference disappeared with time. CBD decreased IL-33 + cells in B6 by 70% while nearly increasing CTGF + cells in db/db mice by two folds from 18.6% to 38.8% (p < 0.05) using a dorsal wound model. We review the current literature on normal and abnormal wound healing, and document effects of CBD in B6 and db/db dorsal cutaneous wounds. CBD may have some beneficial effects in diabetic wounds. We applied 6–mm circular punch to create standard size full-thickness dorsal wounds in B6 and db/db mice. The experimental group received CBD while the control group got only vehicle. The outcome measures were rate of wound closure, wound cells expressing IL-33 and CTGF, and ILC profiles. In B6, the initial rate of wound closure was slower but there was no delay in the time to final closure, and cells expressing IL-33 was significantly reduced. CTGF + cells were higher in db/bd wounds treated with CBD. These data support the potential use of CBD to improve diabetic cutaneous wound healing. Full article

Chronic exposure to harmful pollutants, chemicals, and pathogens from the environment can lead to pathological changes in the epithelial barrier, which increase the risk of developing an allergy. During allergic inflammation, epithelial cells send proinflammatory signals to group 2 innate lymphoid cell (ILC2s) and eosinophils, which require energy and resources to mediate their activation, cytokine/chemokine secretion, and mobilization of other cells. This review aims to provide an overview of the metabolic regulation in allergic asthma, atopic dermatitis (AD), and allergic rhinitis (AR), highlighting its underlying mechanisms and phenotypes, and the potential metabolic regulatory roles of eosinophils and ILC2s. Eosinophils and ILC2s regulate allergic inflammation through lipid mediators, particularly cysteinyl leukotrienes (CysLTs) and prostaglandins (PGs). Arachidonic acid (AA)-derived metabolites and Sphinosine-1-phosphate (S1P) are significant metabolic markers that indicate immune dysfunction and epithelial barrier dysfunction in allergy. Notably, eosinophils are promoters of allergic symptoms and exhibit greater metabolic plasticity compared to ILC2s, directly involved in promoting allergic symptoms. Our findings suggest that metabolomic analysis provides insights into the complex interactions between immune cells, epithelial cells, and environmental factors. Potential therapeutic targets have been highlighted to further understand the metabolic regulation of eosinophils and ILC2s in allergy. Future research in metabolomics can facilitate the development of novel diagnostics and therapeutics for future application. Full article

Dietary fibers regulate intestinal barrier function; however, the precise mechanisms remain unclear. This study investigated the effects of psyllium fibers on antimicrobial protein expression, focusing on the type II immunity and tuft cell-group 2 innate lymphoid cell (ILC2) circuit in the small intestine of the mouse. Supplemental psyllium fiber upregulated antimicrobial proteins, such as small proline-rich protein 2A (SPRR2A) and resistin-like beta (RELMβ), in mouse small intestine, evidently affecting cecal microbiota composition. The psyllium fibers also increased the RNA and protein expression of molecules related to ILC2 and tuft cells, such as IL-13, IL-25, DCLK1, Gfi-1b, SH2 domain-containing protein 3C, and Spi-B. In addition, ILC2 inhibitor (disulfiram) and bitter taste receptor blocker administration reduced psyllium-induced SPRR2A and RELMβ expression. Collectively, psyllium supplementation upregulates antimicrobial proteins such as SPRR2A and RELMß via the type II immune response and tuft cell-ILC2 circuit in the mouse small intestine. Full article

The cellular and molecular mechanisms of atherosclerosis are still unclear. Type 2 innate lymphocytes (ILC2) exhibit anti-inflammatory properties and protect against atherosclerosis. This study aimed to elucidate the pathogenesis of atherosclerosis development using atherosclerosis model mice (ApoE KO mice) and mice deficient in IL-33 receptor ST2 (ApoEST2 DKO mice). Sixteen-week-old male ApoE KO and ApoEST2 DKO mice were subjected to an 8-week regimen of a high-fat, high-sucrose diet. Atherosclerotic foci were assessed histologically at the aortic valve ring. Chronic inflammation was assessed using flow cytometry and real-time polymerase chain reaction. In addition, saturated fatty acids (palmitic acid) and IL-33 were administered to human aortic endothelial cells (HAECs) to assess fatty acid metabolism. ApoEST2 DKO mice with attenuated ILC2 had significantly worse atherosclerosis than ApoE KO mice. The levels of saturated fatty acids, including palmitic acid, were significantly elevated in the arteries and serum of ApoEST2 DKO mice. Furthermore, on treating HAECs with saturated fatty acids with or without IL-33, the Oil Red O staining area significantly decreased in the IL-33-treated group compared to that in the non-treated group. IL-33 potentially prevented the accumulation of saturated fatty acids within atherosclerotic foci. Full article