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Asthma has been regarded as an inflammatory disease, and group 2 innate lymphoid cells (ILC2s) are implicated in asthma pathogenesis. However, no strategy is available to block ILC2s function. Efficiency is also limited due to the use of systemic or subcutaneous routes of administration. The purpose of this study was to investigate the effects of nanoparticles targeting suppression of tumorigenicity 2 (ST2), which is the ILC2 receptor, to alleviate lung inflammation in the murine model of asthma. The ultra-small SPIO nanoparticles were firstly synthesized, OVA-induced mice were administered by anti-ST2-conjugated nanoparticles. The inflammatory degree of the lung was investigated by H&E. The percentages of ILC2s and CD4 T cells in bronchoalveolar lavage fluid (BALF) and lung tissue were determined by FACS. Th2-cytokine and OVA-IgE levels were detected by real-time PCR and ELISA, respectively. Treatment with anti-ST2-conjugated nanoparticles significantly alleviated airway inflammation, IL-33 and IL-13 levels and the percentage of CD4 T cells. The percentage of ILC2s was increased, whereas the levels of IL-13 and IL-5 expressed by ILC2s were reduced. In the present study, we demonstrated that anti-ST2-conjugated nanoparticles can efficiently control lung inflammation in OVA-induced mice by reducing the ability of ILC2s to produce IL-5 and IL-13, thereby reducing CD4+T cells. Our study also demonstrated that the nanoparticle delivery system could improve the performance of anti-ST2, which may be used as a strategic tool to expand the current drug market.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by Th2-type inflammation and is associated with dysregulated interleukin-25 (IL-25) expression. Type II innate lymphoid cells (ILC2s), as potential effector cells of IL-25, may contribute to the pathogenesis of CRSwNP. However, their specific role in nasal polyp (NP) tissues, particularly in Chinese patients, remains insufficiently understood. Nasal polyp (NP) tissue and turbinate mucosa (TM) were collected from 37 Chinese CRSwNP patients undergoing surgery. TM samples from 7 patients with pituitary tumors were used as controls. IL-25 expression, Th2 cytokines, phosphorylated STAT3 (p-STAT3), and ILC2 levels were assessed via immunohistochemistry, flow cytometry, and ELISA. Isolated ILC2s from NP tissues were stimulated with IL-25, with or without limonin treatment, to evaluate downstream cytokine production and STAT3 activation. Compared to control TM, both NPs and TM from CRSwNP patients showed elevated IL-25 expression. NP tissues exhibited increased p-STAT3 levels and overexpression of Th2 cytokines. ILC2s were significantly more abundant in NPs and TM of CRSwNP patients. Upon IL-25 stimulation, NP-derived ILC2s produced higher levels of IL-5 and IL-13, accompanied by enhanced STAT3 phosphorylation. Limonin treatment significantly reduced both STAT3 activation and Th2 cytokine production in IL-25-stimulated NP tissues. ILC2s function as key effector cells of IL-25 in CRSwNP, promoting type-2 inflammation via the STAT3 signaling pathway. Limonin attenuates this response and may serve as a promising therapeutic agent for CRSwNP by targeting IL-25/STAT3-driven ILC2 activation.

We elucidated the anti-inflammatory mechanisms of IL-38 in allergic asthma. Human bronchial epithelial cells and eosinophils were cocultured upon stimulation with the viral RLR ligand poly (I:C)/LyoVec or infection-related cytokine TNF-α to induce expression of cytokines/chemokines/adhesion molecules. House dust mite (HDM)-induced allergic asthma and humanized allergic asthma NOD/SCID murine models were established to assess anti-inflammatory mechanisms in vivo. IL-38 significantly inhibited induced proinflammatory IL-6, IL-1β, CCL5, and CXCL10 production, and antiviral interferon-β and intercellular adhesion molecule-1 expression in the coculture system. Mass cytometry and RNA-sequencing analysis revealed that IL-38 could antagonize the activation of the intracellular STAT1, STAT3, p38 MAPK, ERK1/2, and NF-κB pathways, and upregulate the expression of the host defense-related gene POU2AF1 and anti-allergic response gene RGS13 . Intraperitoneal injection of IL-38 into HDM-induced allergic asthma mice could ameliorate airway hyperreactivity by decreasing the accumulation of eosinophils in the lungs and inhibiting the expression of the Th2-related cytokines IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluid (BALF) and lung homogenates. Histological examination indicated lung inflammation was alleviated by reductions in cell infiltration and goblet cell hyperplasia, together with reduced Th2, Th17, and innate lymphoid type 2 cell numbers but increased proportions of regulatory T cells in the lungs, spleen, and lymph nodes. IL-38 administration suppressed airway hyperreactivity and asthma-related IL-4 and IL-5 expression in humanized mice, together with significantly decreased CCR3 + eosinophil numbers in the BALF and lungs, and a reduced percentage of human CD4 + CRTH2 + Th2 cells in the lungs and mediastinal lymph nodes. Together, our results demonstrated the anti-inflammatory mechanisms of IL-38 and provided a basis for the development of a regulatory cytokine-based treatment for allergic asthma.

Millions of people worldwide are suffering from allergic inflammatory airway disorders. These conditions are regarded as a consequence of multiple imbalanced immune events resulting in an inadequate response with the exact underlying mechanisms still being a subject of ongoing research. Several cell populations have been proposed to be involved but it is becoming increasingly evident that group 2 innate lymphoid cells (ILC2s) play a key role in the initiation and orchestration of respiratory allergic inflammation. ILC2s are important mediators of inflammation but also tissue remodeling by secreting large amounts of signature cytokines within a short time period. Thereby, ILC2s instruct innate but also adaptive immune responses. Here, we will discuss the recent literature on allergic inflammation of the respiratory tract with a focus on ILC2 biology. Furthermore, we will highlight different therapeutic strategies to treat pulmonary allergic inflammation and their potential influence on ILC2 function as well as discuss the perspective of using human ILC2s for diagnostic purposes.

Allergic Rhinitis (AR) is a highly prevalent type 2 inflammatory disease driven by a complex immunogenetic background. This review aims to systematically delineate the immunogenetic landscape of AR, elucidating the complete knowledge chain from macroscopic cellular interactions and microscopic molecular regulation to precision targeted therapies. The article first dissects the two core immune axes driving the pathological process of AR: one is the classic adaptive immune pathway, centered on Th2 cells, which mediates IgE production, eosinophil infiltration, and mucus hypersecretion through the secretion of cytokines such as IL-4, IL-5, and IL-13; the other is the innate immune initiation pathway, in which nasal epithelial cells act as \"sentinels\" by releasing \"alarmins\" like TSLP and IL-33, leading to the rapid activation of type 2 innate lymphoid cells (ILC2s). The review then delves into the sophisticated signaling networks that regulate these immune responses, with a particular focus on the classic IL-4/STAT6/GATA3 signaling axis and its negative regulatory mechanisms. Building on this, the article further elaborates on the genetic susceptibility architecture of AR, highlighting key risk loci identified by genome-wide association studies (GWAS), such as variants in antigen presentation genes (HLA), epithelial barrier genes (FLG), and genes related to cytokine signaling pathways. To connect genetics with the environment, this review systematically summarizes epigenetic regulatory mechanisms, including DNA methylation, histone modifications, and microRNAs (miRNAs), and discusses the long-range immunomodulatory effects of nasal and gut microbiota dysbiosis on AR via the \"gut-nasal axis\". Finally, from a translational medicine perspective, the article demonstrates how a profound understanding of these pathophysiological mechanisms has successfully spurred the development of highly effective targeted biologics, such as omalizumab (targeting IgE), dupilumab (targeting the IL-4Rα receptor, thus blocking IL-4/IL-13 signaling), and tezepelumab (targeting TSLP). This review integrates the latest multidimensional research advances in immunology, genetics, epigenetics, and microbiome studies of AR, providing a comprehensive theoretical framework for understanding its complex pathogenesis and for the development of future personalized treatment strategies.

Renifolin F is a prenylated chalcone isolated from Shuteria involucrata, a traditional minority ethnic medicine used to treat the respiratory diseases and asthma. Based on the effects of the original medicine plant, we established an in vivo mouse model of allergic asthma using ovalbumin (OVA) as an inducer to evaluate the therapeutic effects of Renifolin F. In the research, mice were sensitized and challenged with OVA to establish an allergic asthma model to evaluate the effects of Renifolin F on allergic asthma. The airway hyper-reactivity (AHR) to methacholine, cytokine levels, ILC2s quantity and mircoRNA-155 expression were assessed. We discovered that Renifolin F attenuated AHR and airway inflammation in the OVA-induced asthmatic mouse model by inhibiting the regulation of ILC2s in the lung, thereby, reducing the upstream inflammatory cytokines IL-25, IL-33 and TSLP; the downstream inflammatory cytokines IL-4, IL-5, IL-9 and IL-13 of ILC2s; and the co-stimulatory factors IL-2 and IL-7; as well as the expression of microRNA-155 in the lung. The findings suggest a therapeutic potential of Renifolin F on OVA-induced airway inflammation.

The alarmin IL-33 has been implicated in the pathology of immune-mediated liver diseases. IL-33 activates regulatory T cells (Tregs) and type 2 innate lymphoid cells (ILC2s) expressing the IL-33 receptor ST2. We have previously shown that endogenous IL-33/ST2 signaling activates ILC2s that aggravate liver injury in murine immune-mediated hepatitis. However, treatment of mice with exogenous IL-33 before induction of hepatitis ameliorated disease severity. Since IL-33 induces expression of amphiregulin (AREG) crucial for Treg function, we investigated the immunoregulatory role of the ST2 Treg/AREG axis in immune-mediated hepatitis. C57BL/6, ST2-deficient (Il1rl1 ) and Areg mice received concanavalin A to induce immune-mediated hepatitis. Foxp3Cre x ST2fl/fl mice were pre-treated with IL-33 before induction of immune-mediated hepatitis. Treg function was assessed by adoptive transfer experiments and suppression assays. The effects of AREG and IL-33 on ST2 Tregs and ILC2s were investigated . Immune cell phenotype was analyzed by flow cytometry. We identified IL-33-responsive ST2 Tregs as an effector Treg subset in the murine liver, which was highly activated in immune-mediated hepatitis. Lack of endogenous IL-33 signaling in Il1rl1 mice aggravated disease pathology. This was associated with reduced Treg activation. Adoptive transfer of exogenous IL-33-activated ST2 Tregs before induction of hepatitis suppressed inflammatory T-cell responses and ameliorated disease pathology. We further showed increased expression of AREG by hepatic ST2 Tregs and ILC2s in immune-mediated hepatitis. Areg mice developed more severe liver injury, which was associated with enhanced ILC2 activation and less ST2 Tregs in the inflamed liver. Exogenous AREG suppressed ILC2 cytokine expression and enhanced ST2 Treg activation . In addition, Tregs from Areg mice were impaired in their capacity to suppress CD4 T-cell activation . Moreover, application of exogenous IL-33 before disease induction did not protect Foxp3Cre x ST2fl/fl mice lacking ST2 Tregs from immune-mediated hepatitis. In summary, we describe an immunoregulatory role of the ST2 Treg/AREG axis in immune-mediated hepatitis, in which AREG suppresses the activation of hepatic ILC2s while maintaining ST2 Tregs and reinforcing their immunosuppressive capacity in liver inflammation.

Background The study investigated the effects and underlying mechanisms of intestinal flora metabolite butyrate on inflammatory ILC2 cells (iILC2s)-mediated lung inflammation in chronic obstructive pulmonary disease (COPD). Methods Mouse models of COPD and acute exacerbation of COPD (AECOPD) were established. Flow cytometry was used to detect natural ILC2 cells (nILC2s) and iILC2s in lung and colon tissues. The 16s rRNA and GC-MS were used to detect microbial flora and short chain fatty acids (SCFAs) in feces. ELISA was used to detect IL-13 and IL-4. Western blot and qRT-PCR were used to detect the relative protein and mRNA levels, respectively. In vitro experiments were performed with sorted ILC2s from colon tissues of control mice. Mice with AECOPD were treated with butyrate. Results The nILC2s and iILC2s in lung and colon tissues of AECOPD mice were significantly higher than control groups. The abundance of the flora Clostridiaceae was significantly reduced, and the content of SCFAs, including acetate and butyrate, was significantly reduced. The in vitro experiments showed that butyrate inhibited iILC2 cell phenotype and cytokine secretion. Butyrate treatment reduced the proportion of iILC2 cells in the colon and lung tissues of mice with AECOPD. Conclusions The nILC2s and iILC2s in the colon tissues are involved in the course of COPD. Decreased Clostridiaceae and butyrate in AECOPD mice caused the accumulation of iILC2 cells in the intestines and lungs. Supplementation of butyrate can reduce iILC2 in the intestine and lung tissues. Our data may provide new ideas for prevention and treatment of COPD.

Group 2 innate lymphoid cells (ILC2s), characterized by a lack of antigen receptors, have been regarded as an important component of type 2 pulmonary immunity. Analogous to Th2 cells, ILC2s are capable of releasing type 2 cytokines and amphiregulin, thus playing an essential role in a variety of diseases, such as allergic diseases and virus-induced respiratory diseases. Interferons (IFNs), an important family of cytokines with potent antiviral effects, can be triggered by microbial products, microbial exposure, and pathogen infections. Interestingly, the past few years have witnessed encouraging progress in revealing the important role of IFNs and IFN-producing cells in modulating ILC2 responses in allergic lung inflammation and respiratory viral infections. This review underscores recent progress in understanding the role of IFNs and IFN-producing cells in shaping ILC2 responses and discusses disease phenotypes, mechanisms, and therapeutic targets in the context of allergic lung inflammation and infections with viruses, including influenza virus, rhinovirus (RV), respiratory syncytial virus (RSV), and severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2).

Mucosal-associated invariant T (MAIT) cells, a blossoming member of the innate-like T cells, play a pivotal role in host defense through engaging the mucosal immunity. Although it has been suggested that MAIT cells are somehow implicated in the allergic airway inflammation mediated by group 2 innate lymphoid cells (ILC2s) such as asthma, the precise role(s) of MAIT cells in such inflammation has remained elusive. To explore the possible roles of MAIT cells in the inflammation, we examined whether MAIT cells suppressed the production of T helper (Th) 2 and inflammatory cytokines from ILC2s, and constrained the proliferation of ILC2s, both of which are prerequisite for airway inflammation. Given that laboratory mice are poor at MAIT cells, a novel mouse line rich in MAIT cells was used. We found that mice rich in MAIT cells showed alleviated airway inflammation as evidenced by reduced infiltration of the immune cells and hyperplasia in goblet cells in the lung concomitant with compromised production of Th2 and inflammatory cytokines, while wild type mice exhibited severe inflammation upon challenge with the fungal extracts. In vitro coculture experiments using purified ILC2s and MAIT cells unrevealed that cytokine-stimulated MAIT cells suppressed ILC2s to produce the cytokines as well as to proliferate most likely via production of IFN-γ. Furthermore, reconstitution of the allergic airway inflammation in the highly immunocompromised mice showed that ILC2-mediated inflammation was alleviated in mice that received MAIT cells along with ILC2s. We concluded that MAIT cells played a crucial role in suppressing the cytokine-producing capacity of ILC2s and ILC2 proliferation, that ultimately led to decrease in the allergic airway inflammation. The results open up a novel therapeutic horizon in ILC2-mediated inflammatory diseases by modulating MAIT cell activity.