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Olfactory dysfunction (OD) is a debilitating symptom frequently reported by patients with chronic rhinosinusitis (CRS) and it is associated with a dysregulated sinonasal inflammation. However, little information is available about the effect of the inflammation-related nasal microbiota and related metabolites on the olfactory function in these patients. Therefore, the current study aimed to investigate the nasal microbiota-metabolites-immune interactions and their role in the pathogenesis of OD in CRS patients. 23 and 19 CRS patients with and without OD, respectively, were enrolled in the present study. The \"Sniffin' Sticks\" was used to measure the olfactory function, while the metagenomic shotgun sequencing and the untargeted metabolite profiling were performed to assess the differences in terms of the nasal microbiome and metabolome between the two groups. The levels of nasal mucus inflammatory mediators were investigated by a multiplex flow Cytometric Bead Array (CBA). A decreased diversity in the nasal microbiome from the OD group compared to the NOD group was evidenced. The metagenomic analysis revealed a significant enrichment of in the OD group, while , , and were significantly less represented (LDA value > 3, p < 0.05). The nasal metabolome profiles were significantly different between the OD and NOD groups ( < 0.05). The purine metabolism was the most significantly enriched metabolic subpathway in OD patients compared with NOD patients ( < 0.001). The expressions of IL-5, IL-8, MIP-1α, MCP-1, and TNF were statistically and significantly increased in the OD group ( < 0.05). All these data, including the dysregulation of the nasal microbiota, differential metabolites, and elevated inflammatory mediators in OD patients demonstrated a clear interaction relationship. The disturbed nasal microbiota-metabolite-immune interaction networks may be implicated in the pathogenesis of OD in CRS patients and the underlying pathophysiological mechanisms need to be further investigated in future studies.

The type 2 immune response is critical for host defense against large parasites such as helminths. On the other hand, dysregulation of the type 2 immune response may cause immunopathological conditions, including asthma, atopic dermatitis, rhinitis, and anaphylaxis. Thus, a balanced type 2 immune response must be achieved to mount effective protection against invading pathogens while avoiding immunopathology. The classical model of type 2 immunity mainly involves the differentiation of type 2 T helper (Th2) cells and the production of distinct type 2 cytokines, including interleukin-4 (IL-4), IL-5, and IL-13. Group 2 innate lymphoid cells (ILC2s) were recently recognized as another important source of type 2 cytokines. Although eosinophils, mast cells, and basophils can also express type 2 cytokines and participate in type 2 immune responses to various degrees, the production of type 2 cytokines by the lymphoid lineages, Th2 cells, and ILC2s in particular is the central event during the type 2 immune response. In this review, we discuss recent advances in our understanding of how ILC2s and Th2 cells orchestrate type 2 immune responses through direct and indirect interactions.

Coronavirus disease 2019 (COVID-19) is a global pandemic infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and abnormal, overactivated innate immunity and “cytokine storms” have been proposed as potential pathological mechanisms for rapid COVID-19 progression. Theoretically, asthmatic patients should have increased susceptibility and severity for SARS-CoV-2 infection due to a deficient antiviral immune response and the tendency for exacerbation elicited by common respiratory viruses. However, existing studies have not shown an expected prevalence of asthmatic individuals among COVID-19 patients. Certain aspects of type 2 immune response, including type 2 cytokines (IL-4, IL-13, etc.) and accumulation of eosinophils, might provide potential protective effects against COVID-19. Furthermore, conventional therapeutics for asthma, including inhaled corticosteroids, allergen immunotherapy (AIT), and anti-IgE monoclonal antibody, might also reduce the risks of asthmatics suffering infection of the virus through alleviating inflammation or enhancing antiviral defense. The interactions between COVID-19 and asthma deserve further attention and clarification.

The function of type 2 immunity and mechanisms underlying the initiation of type 2 immunity after sepsis-induced lung injury remain unclear. Sphingosine-1-phosphate receptor 2 (S1PR2) has been demonstrated to modulate type 2 immunity in the context of asthma and pulmonary fibrosis. Thus, this study aims to investigate the role of type 2 immunity and whether and how S1PR2 regulates type 2 immunity in sepsis. Peripheral type 2 immune responses in patients with sepsis and healthy control subjects were assessed. The impact of S1PR2 on type 2 immunity in patients with sepsis and in a murine model of sepsis was further investigated. The type 2 innate immune responses were significantly increased in the circulation of patients 24 hours after sepsis, which was positively related to clinical complications and negatively correlated with S1PR2 mRNA expression. Animal studies showed that genetic deletion or pharmacological inhibition of S1PR2 induced type 2 innate immunity accumulation in the post-septic lungs. Mechanistically, S1PR2 deficiency promoted macrophage-derived interleukin (IL)-33 increase and the associated type 2 response in the lung. Furthermore, S1PR2-regulated IL-33 from macrophages mitigated lung injury after sepsis in mice. In conclusion, a lack of S1PR2 modulates the type 2 immune response by upregulating IL-33 release from macrophages and alleviates sepsis-induced lung injury. Targeting S1PR2 may have potential therapeutic value for sepsis treatment.

Different human and animal pathogens trigger distinct immune responses in their hosts. The infection of bacteria or viruses can trigger type I pro-inflammatory immune responses (e.g., IFN-γ, TNF-α, T H 1 cells), whereas infection by helminths typically elicits a type II host resistance and tolerizing immune response (e.g., IL-4, IL-5, IL-13, T H 2 cells). In some respects, the type I and II immune responses induced by these different classes of pathogens are antagonistic. Indeed, recent studies indicate that infection by helminths differentially shapes the response and outcome of subsequent infection by viruses and bacteria. In this review, we summarize the current knowledge on how helminth infections influence concurrent or subsequent microbial infections and also discuss the implications for helminth-mediated immunity on the outcome of SARS-CoV-2 disease.

Inflammation is a tissue response to a variety of harmful stimuli, such as pathogens, irritants, and injuries, and can eliminate insults and limit tissue damage. However, dysregulated inflammation is recognized as a cause of many human diseases, exemplified by organ fibrosis and cancer. In this regard, inflammation-promoted fibrosis is commonly observed in human lung diseases, such as idiopathic pulmonary fibrosis and pneumoconiosis. Carbon nanotubes (CNTs) are a type of nanomaterials with unique properties and various industrial and commercial applications. On the other hand, certain forms of CNTs are potent inducers of inflammation and fibrosis in animal lungs. Notably, acute inflammation is a remarkable phenotype elicited by CNTs in the lung during the early acute phase post-exposure; whereas a type 2 immune response is evidently activated and dominates during the late acute and chronic phases, leading to type 2 inflammation and lung fibrosis. Numerous studies demonstrate that these immune responses involve distinct immune cells, various pathologic factors, and specific functions and play crucial roles in the initiation and progression of inflammation and fibrosis in the lung exposed to CNTs. Thus, the mechanistic understanding of the immune responses activated by CNTs has drawn great attention in recent years. This article reviews the major findings on the cell signaling pathways that are activated in immune cells and exert functions in promoting immune responses in CNT-exposed lungs, which would provide new insights into the understanding of CNT-induced lung inflammation and inflammation-driven fibrosis, the application of CNT-induced lung inflammation and fibrosis as a new disease model, and the potential of targeting immune cells as a therapeutic strategy for relevant human lung diseases.

Summary Gastrointestinal nematode infections elicit robust type 2 immune responses that facilitate rapid parasite expulsion. Our previous studies demonstrated that 18-month-old mice exhibit both impaired nematode clearance and reduced type 2-cytokine production, suggesting that aging diminishes the host’s potential to mount effective immune defenses. To further investigate the underlying mechanisms, we compared young (3 months old) and aged mice (18 months old) infected with the nematode Heligmosomoides polygyrus (Hp), focusing on the interplay between type 2 immune responses and intestinal ecology. Hp infected young mice exhibited increased expression of Th2 cytokines (e.g., il-4 ) and short-chain fatty acid (SCFA) receptors GPR41/GPR43, while these responses were markedly diminished in aged mice. Correspondingly, cecal SCFA levels—particularly acetate and propionate—increased in Hp infected young mice but decreased in aged counterparts. Moreover, Hp infection induced a pronounced shift in the cecal microbiota composition of young mice, notably a reduced Bacillota/Bacteroidota ratio (F/B) ratio, a change much less evident in aged mice. These findings suggest that the age-related decline in type 2 immune responses to gastrointestinal nematode infection is linked to reduced gut microbiota responsiveness, which may compromise host resistance to the gastrointestinal parasites.

The initiation of type 2 immune responses at mucosal barriers is regulated by rapidly secreted cytokines called alarmins. The alarmins IL-33, IL-25 and TSLP are mainly secreted by stromal and epithelial cells in tissues and were linked to chronic inflammatory diseases, such as allergic lung inflammation, or to resistance against worm infections. Receptors for alarmins are expressed by a variety of immune cells, including group 2 innate lymphoid cells (ILC2s), an early source of the type 2 cytokines, such as IL-5 and IL-13, which have been linked to atopic diseases and anti-worm immunity as well. However, the precise contribution of the IL-33 receptor signals for ILC2 activation still needs to be completed due to limitations in targeting genes in ILC2. Using the newly established Nmur1 iCre-eGFP mouse model, we obtained specific conditional genetic ablation of the IL-33 receptor subunit ST2 in ILC2s. ST2-deficient ILC2s were unresponsive to IL-33 but not to stimulation with the alarmin IL-25. As a result of defective ST2 signals, ILC2s produced limited amounts of IL-5 and IL-13 and failed to support eosinophil homeostasis. Further, ST2-deficient ILC2s were unable to expand and promote the recruitment of eosinophils during allergic lung inflammation provoked by papain administration. During infection with Nippostrongylus brasiliensis , ILC2-intrinsic ST2 signals were required to mount an effective type 2 immune response against the parasite leading to higher susceptibility against worm infection in conditional knockout mice. Therefore, this study argues for a non-redundant role of cell-intrinsic ST2 signals triggering proper activation of ILC2 for initiation of type 2 immunity.

Intestinal tuft cells, a chemosensory cell type in mucosal epithelia that secrete interleukin (IL)-25, play a pivotal role in type 2 immune responses triggered by parasitic infections. Tuft cell-derived IL-25 activates type 2 innate lymphoid cells (ILC2) to secrete IL-13, which, in turn, acts on intestinal stem or transient amplifying cells to expand tuft cells themselves and mucus-secreting goblet cells. However, the molecular mechanisms of tuft cell differentiation under type 2 immune responses remain unclear. The present study investigated the effects of the deletion of activating transcription factor 5 (ATF5) on the type 2 immune response triggered by succinate (a metabolite of parasites) in mice. ATF5 mRNAs were expressed in the small intestine, and the loss of the ATF5 gene did not affect the gross morphology of the tissue or the basal differentiation of epithelial cell subtypes. Succinate induced marked increases in tuft and goblet cell numbers in the ATF5-deficient ileum. Tuft cells in the ATF5-deficient ileum are assumed to be a subtype of intestinal tuft cells (Tuft-2 cells) marked by the transcription factor Spib. Exogenous IL-25 induced similar increases in tuft and goblet cell numbers in wild-type and ATF5-deficient ilea. IL-13 at a submaximal dose enhanced tuft cell differentiation more in ATF5-deficient than in wild-type intestinal organoids. These results indicate that the loss of ATF5 enhanced the tuft cell-ILC2 type 2 immune response circuit by promoting tuft cell differentiation in the small intestine, suggesting its novel regulatory role in immune responses against parasitic infections.

T helper (Th) 2-dependent type 2 immune pathways have been recognized as an important driver for the development of fibrosis. Upon stimulation, activated Th2 immune cells and type 2 cytokines interact with inflammatory and tissue repair functions to stimulate an overzealous reparative response to tissue damage, leading to organ fibrosis and destruction. In this connection, type 2 pathways are activated by a variety of insults and pathological conditions to modulate the response. Carbon nanotubes (CNTs) are nanomaterials with a wide range of applications. However, pulmonary exposure to CNTs causes a number of pathologic outcomes in animal lungs, dominated by inflammation and fibrosis. These findings, alongside the rapidly expanding production and commercialization of CNTs and CNT-containing materials in recent years, have raised concerns on the health risk of CNT exposure in humans. The CNT-induced pulmonary fibrotic lesions resemble those of human fibrotic lung diseases, such as idiopathic pulmonary fibrosis and pneumoconiosis, to a certain extent with regard to disease development and pathological features. In fibrotic scenarios, immune cells are activated including varying immune pathways, ranging from innate immune cell activation to autoimmune disease. These events often precede and/or accompany the occurrence of fibrosis. Upon CNT exposure, significant induction and activation of Th2 cells and type 2 cytokines in the lungs are observed. Moreover, type 2 pathways are shown to play important roles in promoting CNT-induced lung fibrosis by producing type 2 pro-fibrotic factors and inducing the reparative phenotypes of macrophages in response to CNTs. In light of the vastly increased demand for nanosafety and the apparent induction and multiple roles of type 2 immune pathways in lung fibrosis, we review the current literature on CNT-induced lung fibrosis, with a focus on the induction and activation of type 2 responses by CNTs and the stimulating function of type 2 signaling on pulmonary fibrosis development. These analyses provide new insights into the mechanistic understanding of CNT-induced lung fibrosis, as well as the potential of using type 2 responses as a monitoring target and therapeutic strategy for human fibrotic lung disease.