CD4+ T helper 2 (Th2) cells and group 2 innate lymphoid cells (ILC2s) drive type 2 immune responses via similar effector molecules that are primarily induced by different signals-interleukin (IL)-33 in ILC2s and TCR engagement in Th2 cells. Here, we examined the transcriptional regulation of type 2 immunity, focusing on the NF-κB pathway, which is differentially activated by TCR engagement or cytokine signaling. Conditional deletion of the NF-κB subunits c-Rel and p65 limited the expression of key type 2 genes, including Il13 and Il5, in ILC2s but not in Th2 cells. Genome-wide analysis revealed that the regulatory regions of such genes exist in an open chromatin state in ILC2s, allowing NF-κB binding upon IL-33 stimulation. These regions are less accessible in unstimulated Th2 cells, where NFAT plays a dominant role. Accordingly, p65 deletion impaired ILC2 activation and function during airway inflammation and helminth infection. Thus, innate and adaptive lymphocytes leverage distinct epigenetic landscapes and transcriptional regulators to control shared effector genes.

The serotonin (5-hydroxytryptamine) system represents a crucial neurotransmitter network that regulates mood, behavior, and cognitive functions, playing a significant role in the pathogenesis and progression of depression. Although this perspective faces significant challenges, the serotonin system continues to exert substantial modulatory effects on specific aspects of psychological functioning and actively contributes to multiple pathological processes in depression development. Therefore, this review systematically integrates interdisciplinary research advances regarding the relationship between the 5-hydroxytryptamine (5-HT) system and depression. By focusing on core biological processes including serotonin biosynthesis and metabolism, SERT gene regulatory networks, and protein molecular modifications, it aims to elucidate how 5-HT system dysregulation contributes to the development of depression, while providing novel research perspectives and therapeutic targets for innovative antidepressant drug development.

Group 2 Innate Lymphoid Cells (ILC2s) have recently been shown to exert key regulatory functions in both innate and adaptive immune response networks that drive the establishment and progression of type 2 immunity. Although mainly tissue resident, ILC2s and their crosstalk within tissue microenvironments influence metabolism at both the local and systemic levels. In turn, the energetic demand and metabolic status within these systems shape the diverse phenotypes and effector functions of ILC2s. Deciphering these metabolic networks in ILC2s is therefore essential in understanding their various roles in health as well as their associated pathophysiologies. Here we detail a framework of experimental approaches to study key immunometabolic states of primary murine ILC2s and link them to unique phenotypes and their corresponding functionality. Utilizing flow cytometry, Single Cell ENergetic metabolism by profilIng Translation inHibition (SCENITH), and the Seahorse platform we provide a framework that allows in-depth analysis of cellular bioenergetic states to determine the immunometabolic wiring of ILC2s. Connecting immunometabolic states and networks to ILC2 phenotypes and effector functions with this method will allow future in-depth studies to assess the potential of novel pharmaceutics in altering ILC2 functionality in clinical settings.

Asthma is a common chronic inflammatory disease of the airways. A substantial number of patients present with severe and therapy-resistant asthma, for which the underlying biological mechanisms remain poorly understood. In most asthma patients, airway inflammation is characterized by chronic activation of type 2 immunity. CD4+ T helper 2 (Th2) cells are the canonical producers of the cytokines that fuel type 2 inflammation: interleukin (IL)-4, IL-5, IL-9, and IL-13. However, more recent findings have shown that other lymphocyte subsets, in particular group 2 innate lymphoid cells (ILC2s) and type 2 CD8+ cytotoxic T (Tc2) cells, can also produce large amounts of type 2 cytokines. Importantly, a substantial number of severe therapy-resistant asthma patients present with chronic type 2 inflammation, despite the high sensitivity of Th2 cells for suppression by corticosteroids-the mainstay drugs for asthma. Emerging evidence indicates that ILC2s and Tc2 cells are more abundant in severe asthma patients and can adopt corticosteroid-resistance states. Moreover, many severe asthma patients do not present with overt type 2 airway inflammation, implicating non-type 2 immunity as a driver of disease. In this review, we will discuss asthma pathophysiology and focus on the roles played by ILC2s, Tc2 cells, and non-type 2 lymphocytes, placing special emphasis on severe disease forms.

Tertiary lymphoid structures (TLSs) are de novo ectopic lymphoid aggregates that regulate immunity in chronically inflamed tissues, including tumours. Although TLSs form due to inflammation-triggered activation of the lymphotoxin (LT)-LTβ receptor (LTβR) pathway1, the inflammatory signals and cells that induce TLSs remain incompletely identified. Here we show that interleukin-33 (IL-33), the alarmin released by inflamed tissues2, induces TLSs. In mice, Il33 deficiency severely attenuates inflammation- and LTβR-activation-induced TLSs in models of colitis and pancreatic ductal adenocarcinoma (PDAC). In PDAC, the alarmin domain of IL-33 activates group 2 innate lymphoid cells (ILC2s) expressing LT that engage putative LTβR+ myeloid organizer cells to initiate tertiary lymphoneogenesis. Notably, lymphoneogenic ILC2s migrate to PDACs from the gut, can be mobilized to PDACs in different tissues and are modulated by gut microbiota. Furthermore, we detect putative lymphoneogenic ILC2s and IL-33-expressing cells within TLSs in human PDAC that correlate with improved prognosis. To harness this lymphoneogenic pathway for immunotherapy, we engineer a recombinant human IL-33 protein that expands intratumoural lymphoneogenic ILC2s and TLSs and demonstrates enhanced anti-tumour activity in PDAC mice. In summary, we identify the molecules and cells of a druggable pathway that induces inflammation-triggered TLSs. More broadly, we reveal a lymphoneogenic function for alarmins and ILC2s.

Interleukin-10 (IL-10)-producing group 2 innate lymphoid cells (ILC210) regulate inflammatory immune responses, yet their therapeutic potential remains largely unexplored. Here, we demonstrate that cell therapy with human ILC210 inhibits pathogenic T cell responses in humanized mouse models of graft-versus-host disease (GVHD), resulting in reduced GVHD severity and improved overall survival without limiting the graft-versus-leukemia effect. ILC210 conferred superior protection from GVHD than IL-10-/low ILC2s, and blocking IL-10 and IL-4 abrogated ILC210 protective effects, indicating that these cytokines are important for the protective effects of ILC210. Notably, ILC210 provided comparable protection from GVHD to regulatory T cells without impairing T cell engraftment, instead decreasing intestinal T cell infiltration and suppressing CD4+ Th1 and CD8+ Tc1 cells. CITE-seq of expanded ILC2s revealed CD49d and CD86 are markers that allow for enrichment of ILC210 from conventional ILC2s and tracking of ILC210 in patient studies. Altogether, these findings demonstrate the potential of ILC210 in cell therapies for GVHD and other immune-mediated diseases.

Interleukin-33 (IL-33) is a nuclear factor and member of the IL-1 cytokine family. IL-33 is mainly expressed by epithelial and endothelial cells and exerts its function through interaction with various immune cells, and binding to its receptor can form the IL-33/Suppression of tumorigenicity 2 (ST2) signaling pathway. While most cytokines are actively synthesized within cells, IL-33 is produced passively in response to tissue damage or cell necrosis, indicating its role as a signaling molecule following cellular infection, stress, or trauma. IL-33/ST2 signaling pathway has been proved to play diverse role in the pathological process of central nervous system disorders, cancer, fibrosis, autoimmune diseases, etc. Although research on the IL-33/ST2 signaling pathway has deepened recently, relevant treatment strategies have been proposed, and even targeted drugs are in the preclinical stage; further research on the effect of the IL-33/ST2 signaling pathway in different diseases is still necessary, to provide a clearer understanding of the different roles of IL-33/ST2 in disease progression and to develop new drugs and treatment strategies. Because IL-33/ST2 plays an important role in the occurrence and progression of diseases, the study of therapeutic drugs targeting this pathway is also necessary. This review focused on recent studies on the positive or negative role of IL-33/ST2 in different diseases, as well as the current related drugs targeting IL-33/ST2 in the preclinical and clinical stage. The mechanism of IL-33/ST2 in different diseases and its mediating effect on different immune cells have been summarized, as well as the antibody drugs targeting IL-33 or ST2, natural compounds with a mediating effect, and small molecule substances targeting relative pathway. We aim to provide new ideas and treatment strategies for IL-33/ST2-related drugs to treat different diseases.

The aim of this study was to investigate the role of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exo) in regulating the intestinal type 2 immune response for either protection or therapy.

hUCMSC-Exo was considered a novel cell-free therapeutic product that shows promise in the treatment of various diseases. Type 2 immunity is a protective immune response classified as T-helper type 2 (Th2) cells and is associated with helminthic infections and allergic diseases. The effect of hUCMSC-Exo on intestinal type 2 immune response is not clear.

C57BL/6 mice were used to establish intestinal type 2 immune response by administering of H. poly and treated with hUCMSC-Exo before or after H. poly infection. Intestinal organoids were isolated and co-cultured with IL-4 and hUCMSC-Exo. Then, we monitored the influence of hUCMSC-Exo on type 2 immune response by checking adult worms, the hyperplasia of tuft and goblet cells Result: hUCMSC-Exo significantly delays the colonization of H. poly in subserosal layer of duodenum on day 7 post-infection and promotes the hyperplasia of tuft cells and goblet cells on day 14 post-infection. HUCMSC-Exo enhances the expansion of tuft cells in IL-4 treated intestinal organoids, and promotes lytic cell death.

Our study demonstrates hUCMSC-Exo may benefit the host by increasing the tolerance at an early infection stage and then enhancing the intestinal type 2 immune response to impede the helminth during Th2 priming. Our results show hUCMSC-Exo may be a positive regulator of type 2 immune response, suggesting hUCMSC-Exo has a potential therapeutic effect on allergic diseases.

The intestine is characterized by an environment in which host requirements for nutrient and water absorption are consequently paired with the requirements to establish tolerance to the outside environment. To better understand how the intestine functions in health and disease, large efforts have been made to characterize the identity and composition of cells from different intestinal regions1-8. However, the robustness, nature of adaptability and extent of resilience of the transcriptional landscape and cellular underpinning of the intestine in space are still poorly understood. Here we generated an integrated resource of the spatial and cellular landscape of the murine intestine in the steady and perturbed states. Leveraging these data, we demonstrated that the spatial landscape of the intestine was robust to the influence of the microbiota and was adaptable in a spatially restricted manner. Deploying a model of spatiotemporal acute inflammation, we demonstrated that both robust and adaptable features of the landscape were resilient. Moreover, highlighting the physiological relevance and value of our dataset, we identified a region of the middle colon characterized by an immune-driven multicellular spatial adaptation of structural cells to the microbiota. Our results demonstrate that intestinal regionalization is characterized by robust and resilient structural cell states and that the intestine can adapt to environmental stress in a spatially controlled manner through the crosstalk between immunity and structural cell homeostasis.

The maintenance of intestinal homeostasis is a fundamental process critical for organismal integrity. Sitting at the interface of the gut microbiome and mucosal immunity, adaptive and innate lymphoid populations regulate the balance between commensal micro-organisms and pathogens. Checkpoint inhibitors, particularly those targeting the CTLA-4 pathway, disrupt this fine balance and can lead to inflammatory bowel disease and immune checkpoint colitis. Here, we show that CTLA-4 is expressed by innate lymphoid cells and that its expression is regulated by ILC subset-specific cytokine cues in a microbiota-dependent manner. Genetic deletion or antibody blockade of CTLA-4 in multiple in vivo models of colitis demonstrates that this pathway plays a key role in intestinal homeostasis. Lastly, we have found that this observation is conserved in human IBD. We propose that this population of CTLA-4-positive ILC may serve as an important target for the treatment of idiopathic and iatrogenic intestinal inflammation.

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.

We have previously shown that asthma-like airways inflammation may be induced by topical exposure to respiratory tract pathogens such as S. pneumoniae (SP) in concert with epithelial alarmins such as IL-33. Details of the pathogenesis of this murine surrogate remain however unexplored.

Airways inflammation was induced by repeated, intranasal exposure of Il-4-/-, Rag1-/- and Rag2-/-Il2rg-/- mice (in which B lymphocyte IgE switching, adaptive and innate immunity are respectively ablated) as well as wild type mice to inactivated SP, IL-33 or both. Airways pathological changes were analysed, and the subsets and functions of locally accumulated ILC2s investigated by single cell RNA sequencing and flow cytometry.

In the presence of IL-33, repeated exposure of the airways to inactivated SP caused marked eosinophil- and neutrophil-rich inflammation and local accumulation of ILC2s, which was retained in the Il-4-/- and Rag1-/- deficient mice but abolished in the Rag2-/-Il2rg-/- mice, an effect partly reversed by adoptive transfer of ILC2s. Single cell sequencing analysis of ILC2s recruited following SP and IL-33 exposure revealed a Klrg1+Ly6a+subset, expressing particularly elevated quantities of the pro-inflammatory cytokine IL-6, type 2 cytokines (IL-5 and IL-13) and MHC class II molecules, promoting type 2 inflammation as well as involved in neutrophil-mediated inflammatory responses.

Local accumulation of KLRG1+Ly6a+ ILC2s in the lung tissue is a critical aspect of the pathogenesis of airways eosinophilic and neutrophil-rich inflammation induced by repeated exposure to SP in the presence of the epithelial alarmin IL-33.

Interleukin 33 (IL-33), once predominantly recognized for its pro-tumoral activities, has emerged as a multifunctional cytokine with antitumor properties. IL-33 pleiotropic activities include activation of Th1 CD4+ T cells, CD8+ T cells, NK cells, dendritic cells, eosinophils, as well as type 2 innate lymphoid cells. Regarding this immunomodulatory activity, IL-33 demonstrates synergistic interactions with various cancer therapies, including immune checkpoint blockade and chemotherapy. Combinatorial treatments leveraging IL-33 exhibit enhanced antitumor efficacy across different tumor models, promising novel avenues for cancer therapy. Despite its antitumor effects, the complex interplay of IL-33 within the tumor microenvironment underscores the need for further investigation. Understanding the mechanisms underlying IL-33's dual role as both a promoter and inhibitor of tumor progression is essential for refining therapeutic strategies and fully realizing its potential in cancer immunotherapy. This review delves into the intricate landscape of IL-33 effects within the tumor microenvironment, highlighting its pivotal role in orchestrating immune responses against cancer.

Innate lymphoid cells (ILCs), as newly discovered antigen-independent innate immune cells, respond promptly to stimuli by secreting effector cytokines to exert effector functions similar to those of T cells. ILCs predominantly reside at mucosal sites and play critical roles in defending against infections, maintaining mucosal homeostasis, regulating inflammatory and immune responses, and participating in tumorigenesis. Recently, there has been a growing interest in the role of ILCs in oral diseases. This review outlines the classifications and the major characteristics of ILCs, and then comprehensively expatiates the research on ILCs in oral cancer, primary Sjogren's syndrome, periodontal diseases, oral lichen planus, oral candidiasis, Behcet's disease, and pemphigus vulgaris, aiming at summarising the implications of ILCs in oral diseases and providing new ideas for further research.

Innate lymphoid cells (ILCs) can promote host defense, chronic inflammation, or tissue protection and are regulated by cytokines and neuropeptides. However, their regulation by diet and microbiota-derived signals remains unclear. We show that an inulin fiber diet promotes Tph1-expressing inflammatory ILC2s (ILC2INFLAM) in the colon, which produce IL-5 but not tissue-protective amphiregulin (AREG), resulting in the accumulation of eosinophils. This exacerbates inflammation in a murine model of intestinal damage and inflammation in an ILC2- and eosinophil-dependent manner. Mechanistically, the inulin fiber diet elevated microbiota-derived bile acids, including cholic acid (CA) that induced expression of ILC2-activating IL-33. In IBD patients, bile acids, their receptor farnesoid X receptor (FXR), IL-33, and eosinophils were all upregulated compared with controls, implicating this diet-microbiota-ILC2 axis in human IBD pathogenesis. Together, these data reveal that dietary fiber-induced changes in microbial metabolites operate as a rheostat that governs protective versus pathologic ILC2 responses with relevance to precision nutrition for inflammatory diseases.

The prevalence rate of allergic diseases including asthma, atopic rhinitis (AR) and atopic dermatitis (AD) has been significantly increasing in recent decades due to environmental changes and social developments. With the study of innate lymphoid cells, the crucial role played by type 2 innate lymphoid cells (ILC2s) have been progressively unveiled in allergic diseases. ILC2s, which are a subset of innate lymphocytes initiate allergic responses. They respond swiftly during the onset of allergic reactions and produce type 2 cytokines, working in conjunction with T helper type 2 (Th2) cells to induce and sustain type 2 immune responses. The role of ILC2s represents an intriguing frontier in immunology; however, the intricate immune mechanisms of ILC2s in allergic responses remain relatively poorly understood. To gain a comphrehensive understanding of the research progress of ILC2, we summarize recent advances in ILC2s biology in pathologic allergic inflammation to inspire novel approaches for managing allergic diseases.

Type 2 immune responses form a critical defence against enteric worm infections. In recent years, mouse models have revealed shared and unique functions for group 2 innate lymphoid cells and T helper 2 cells in type 2 immune response to intestinal helminths. Both cell types use similar innate effector functions at the site of infection, whereas each population has distinct roles during different stages of infection. In this Perspective, we review the underlying mechanisms used by group 2 innate lymphoid cells and T helper 2 cells to cooperate with each other and suggest an overarching model of the interplay between these cell types over the course of a helminth infection.

Evolution has created complex mechanisms to sense environmental danger and protect tissues, with the nervous and immune systems playing pivotal roles. These systems work together, coordinating local and systemic reflexes to restore homeostasis in response to tissue injury and infection. By sharing receptors and ligands, they influence the pathogenesis of various diseases. Recently, a less-explored aspect of neuroimmune communication has emerged: the release of neuropeptides from immune cells and cytokines/chemokines from sensory neurons. This article reviews evidence of this unique neuroimmune interplay and its impact on the development of allergy, inflammation, itch, and pain. We highlight the effects of this neuroimmune signaling on vital processes such as host defense, tissue repair, and inflammation resolution, providing avenues for exploration of the underlying mechanisms and therapeutic potential of this signaling.

The gut microbiota promotes immune system development in early life, but the interactions between the gut metabolome and immune cells in the neonatal gut remain largely undefined. Here, we demonstrate that the neonatal gut is uniquely enriched with neurotransmitters, including serotonin, and that specific gut bacteria directly produce serotonin while down-regulating monoamine oxidase A to limit serotonin breakdown. We found that serotonin directly signals to T cells to increase intracellular indole-3-acetaldehdye and inhibit mTOR activation, thereby promoting the differentiation of regulatory T cells, both ex vivo and in vivo in the neonatal intestine. Oral gavage of serotonin into neonatal mice resulted in long-term T cell-mediated antigen-specific immune tolerance toward both dietary antigens and commensal bacteria. Together, our study has uncovered an important role for specific gut bacteria to increase serotonin availability in the neonatal gut and identified a function of gut serotonin in shaping T cell response to dietary antigens and commensal bacteria to promote immune tolerance in early life.

Group 2 innate lymphoid cells (ILC2s) are a type of innate immune cells that produce a large amount of IL-5 and IL-13 and two cytokines that are crucial for various processes such as allergic airway inflammation, tissue repair and tissue homeostasis. It is known that damaged epithelial-derived alarmins, such as IL-33, IL-25 and thymic stromal lymphopoietin (TSLP), are the predominant ILC2 activators that mediate the production of type 2 cytokines. In recent years, abundant studies have found that many factors can regulate ILC2 development and function. Hormones synthesized by the body's endocrine glands or cells play an important role in immune response. Notably, ILC2s express hormone receptors and their proliferation and function can be modulated by multiple hormones during allergic airway inflammation. Here, we summarize the effects of multiple hormones on ILC2-driven allergic airway inflammation and discuss the underlying mechanisms and potential therapeutic significance.

Therapies for bladder cancer patients are limited by side effects and failures, highlighting the need for novel targets to improve disease management. Given the emerging evidence highlighting the key role of innate lymphoid cell subsets, especially type 2 innate lymphoid cells (ILC2s), in shaping the tumor microenvironment and immune responses, we investigated the contribution of ILC2s in bladder tumor development. Using the orthotopic murine MB49 bladder tumor model, we found a strong enrichment of ILC2s in the bladder under steady-state conditions, comparable to that in the lung. However, as tumors grew, we observed an increase in ILC1s but no changes in ILC2s. Targeting ILC2s by blocking IL-4/IL-13 signaling pathways, IL-5, or IL-33 receptor, or using IL-33-deficient or ILC2-deficient mice, did not affect mice survival following bladder tumor implantation. Overall, these results suggest that ILC2s do not contribute significantly to bladder tumor development, yet further investigations are required to confirm these results in bladder cancer patients.

Group 2 innate lymphoid cells (ILC2s) are sentinels of barrier immunity, and their activation by the epithelial alarmins IL-25 and IL-33 is a defining trait. In this study, we identified a role for the chemokine receptor CCR8 in modulating skin ILC2 abundance and activation. CCR8 signaling facilitated IL-25-induced increases in skin and lung ILC2s, ILC2 activation and systemic IL-13 production, and ligand-directed ILC2 entry into skin and lung. CCR8 controlled ILC2 tissue entry in IL-25-treated naive mice, but only transferred bone marrow ILC2 progenitors were equipped to enter the skin, whereas multiple tissue-sourced ILC2s entered the lung. CCR8 selectively regulated IL-33-induced increases in skin ILC2s, their proliferation, and production of IL-13/IL-5, as well as IL-33-responsive transferred ILC2 trafficking only to the skin. Collectively, we illuminate (to our knowledge) novel aspects of CCR8 signaling-regulated ILC2 motility and function, especially in the skin, in response to two hallmark ILC2-activating alarmins.

Group 2 innate lymphoid cells (ILC2s) are crucial in promoting type 2 inflammation that contributes to both anti-parasite immunity and allergic diseases. However, the molecular checkpoints in ILC2s that determine whether to immediately launch a proinflammatory response are unknown. Here, we found that retinoid X receptor gamma (Rxrg) was highly expressed in small intestinal ILC2s and rapidly suppressed by alarmin cytokines. Genetic deletion of Rxrg did not impact ILC2 development but facilitated ILC2 responses and the tissue inflammation induced by alarmins. Mechanistically, RXRγ maintained the expression of its target genes that support intracellular cholesterol efflux, which in turn reduce ILC2 proliferation. Furthermore, RXRγ expression prevented ILC2 response to mild stimulations, including low doses of alarmin cytokine and mechanical skin injury. Together, we propose that RXRγ expression and its mediated lipid metabolic states function as a cell-intrinsic checkpoint that confers the threshold of ILC2 activation in the small intestine.

The aromatic amino acid L-tryptophan (Trp) is essentially metabolized along the host and microbial pathways. While much is known about the role played by downstream metabolites of each pathways in intestinal homeostasis, their role in lung immune homeostasis is underappreciated. Here we have examined the role played by the Trp hydroxylase/5-hydroxytryptamine (5-HT) pathway in calibrating host and microbial Trp metabolism during Aspergillus fumigatus pneumonia. We found that 5-HT produced by mast cells essentially contributed to pathogen clearance and immune homeostasis in infection by promoting the host protective indoleamine-2,3-dioxygenase 1/kynurenine pathway and limiting the microbial activation of the indole/aryl hydrocarbon receptor pathway. This occurred via regulation of lung and intestinal microbiota and signaling pathways. 5-HT was deficient in the sputa of patients with Cystic fibrosis, while 5-HT supplementation restored the dysregulated Trp partitioning in murine disease. These findings suggest that 5-HT, by bridging host-microbiota Trp partitioning, may have clinical effects beyond its mood regulatory function in respiratory pathologies with an inflammatory component.

Intestinal stem cells (ISCs) maintain the epithelial lining of the intestines, but mechanisms regulating ISCs and their niche after damage remain poorly understood. Utilizing radiation injury to model intestinal pathology, we report here that the Interleukin-33 (IL-33)/ST2 axis, an immunomodulatory pathway monitored clinically as an intestinal injury biomarker, regulates intrinsic epithelial regeneration by inducing production of epidermal growth factor (EGF). Three-dimensional imaging and lineage-specific RiboTag induction within the stem cell compartment indicated that ISCs expressed IL-33 in response to radiation injury. Neighboring Paneth cells responded to IL-33 by augmenting production of EGF, which promoted ISC recovery and epithelial regeneration. These findings reveal an unknown pathway of niche regulation and crypt regeneration whereby the niche responds dynamically upon injury and the stem cells orchestrate regeneration by regulating their niche. This regenerative circuit also highlights the breadth of IL-33 activity beyond immunomodulation and the therapeutic potential of EGF administration for treatment of intestinal injury.

Innate lymphoid cells are a mixed population of cells and critical regulators of our innate immune system. According to recent scientific literature, tissue resident innate lymphoid cell subtype 2 has been recognized as an important player of type 2 inflammatory responses, involved in different human malignancies like pancreatic, lung, acute myeloid leukemia, gastrointestinal tract cancer, etc. The current reports have revealed that, among the three main ILC sub types, subtype 2 (ILC 2), as the key regulator of initiating the type 2 inflammatory responses at the tumor microenvironment (TME). This activation of ILC-2 is a very important step for the specific downstream functioning of ILC-2. Priming of ILC-2 with different chemokines involves different cytokine secretion from the activated ILC-2 like IL-4, IL-5, IL-13, IL-9 which induce type 2 inflammatory responses involved in the complex interaction with other immune cells like NK cell, Cytotoxic T cell, MDSC and Treg cell. At the initial stage, ILC-2 activation through IL-33 may induce the anti-tumorigenic effect mediated by ILC-2/eosinophil axis. However, it is also evident that PDG2 (Prostaglandin D2)-mediated activation of ILC-2 induces the ILC-2/MDSC immune suppressive pro-tumorigenic niche at the TME. Here, in this review, we have summarized the function of ILC-2 on cancer immunity based on recent scientific work which indicates ILC-2 plays a dual role and orchestrates the immune responses toward type 2 immunity in different cancer settings.

Neutrophil recruitment from circulation to sites of inflammation is guided by multiple chemoattractant cues emanating from tissue cells, immune cells, and platelets. Here, we focus on the function of one G-protein coupled receptor, GPR35, in neutrophil recruitment. GPR35 has been challenging to study due the description of multiple ligands and G-protein couplings. Recently, we found that GPR35-expressing hematopoietic cells respond to the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). We discuss distinct response profiles of GPR35 to 5-HIAA compared to other ligands. To place the functions of 5-HIAA in context, we summarize the actions of serotonin in vascular biology and leukocyte recruitment. Important sources of serotonin and 5-HIAA are platelets and mast cells. We discuss the dynamics of cell migration into inflamed tissues and how multiple platelet and mast cell-derived mediators, including 5-HIAA, cooperate to promote neutrophil recruitment. Additional actions of GPR35 in tissue physiology are reviewed. Finally, we discuss how clinically approved drugs that modulate serotonin uptake and metabolism may influence 5-HIAA-GPR35 function, and we speculate about broader influences of the GPR35 ligand-receptor system in immunity and disease.

The crosstalk between the immune and neuroendocrine systems is critical for intestinal homeostasis and gut-brain communications. However, it remains unclear how immune cells participate in gut sensation of hormones and neurotransmitters release in response to environmental cues, such as self-lipids and microbial lipids. We show here that lipid-mediated engagement of invariant natural killer T (iNKT) cells with enterochromaffin (EC) cells, a subset of intestinal epithelial cells, promoted peripheral serotonin (5-HT) release via a CD1d-dependent manner, regulating gut motility and hemostasis. We also demonstrated that inhibitory sphingolipids from symbiotic microbe Bacteroides fragilis represses 5-HT release. Mechanistically, CD1d ligation on EC cells transduced a signal and restrained potassium conductance through activation of protein tyrosine kinase Pyk2, leading to calcium influx and 5-HT secretion. Together, our data reveal that by engaging with iNKT cells, gut chemosensory cells selectively perceive lipid antigens via CD1d to control 5-HT release, modulating intestinal and systemic homeostasis.

Huge progress has been made in understanding the biology of innate lymphoid cells (ILC) by adopting several well-known concepts in T cell biology. As such, flow cytometry gating strategies and markers, such as CD90, have been applied to indentify ILC. Here, we report that most non-NK intestinal ILC have a high expression of CD90 as expected, but surprisingly a sub-population of cells exhibit low or even no expression of this marker. CD90-negative and CD90-low CD127+ ILC were present amongst all ILC subsets in the gut. The frequency of CD90-negative and CD90-low CD127+ ILC was dependent on stimulatory cues in vitro and enhanced by dysbiosis in vivo. CD90-negative and CD90-low CD127+ ILC were a potential source of IL-13, IFNγ and IL-17A at steady state and upon dysbiosis- and dextran sulphate sodium-elicited colitis. Hence, this study reveals that, contrary to expectations, CD90 is not constitutively expressed by functional ILC in the gut.

Group 2 innate lymphoid cells (ILC2s) are a category of heterogeneous cells that produce the cytokines IL-5 and IL-13, which mediate the type 2 immune response. However, specific drug targets on lung ILC2s have rarely been reported. Previous studies have shown that type 2 cytokines, such as IL-5 and IL-13, are related to depression. Here, we demonstrated the negative correlation between the depression-associated monoamine neurotransmitter serotonin and secretion of the cytokines IL-5 and IL-13 by ILC2s in individuals with depression. Interestingly, serotonin ameliorates papain-induced lung inflammation by suppressing ILC2 activation. Our data showed that the serotonin receptor HTR2A was highly expressed on ILC2s from mouse lungs and human PBMCs. Furthermore, an HTR2A selective agonist (DOI) impaired ILC2 activation and alleviated the type 2 immune response in vivo and in vitro. Mice with ILC2-specific depletion of HTR2A (Il5cre/+·Htr2aflox/flox mice) abolished the DOI-mediated inhibition of ILC2s in a papain-induced mouse model of inflammation. In conclusion, serotonin and DOI could restrict the type 2 lung immune response, indicating a potential treatment strategy for type 2 lung inflammation by targeting HTR2A on ST2+ ILC2s.