Mucosal Immunology最新文献

Decidual CD8⁺T (dCD8⁺T) cells are pivotal in the maintenance of the delicate balance between immune tolerance towards the fetus and immune resistance against pathogens. The endometrium and decidua represent the uterine environments before and during pregnancy, respectively, yet the composition and phenotypic alterations of uterine CD8⁺T cells in these tissues remain unclear. Using flow cytometry and analysis of transcriptome profiles, we demonstrated that human dCD8⁺T and endometrial CD8⁺T (eCD8⁺T) cells exhibited similar T cell differentiation statuses and phenotypes of tissue infiltrating or residency, compared to peripheral CD8⁺T (pCD8⁺T) cells. However, dCD8⁺T cells showed decreased expression of coinhibitory marker (PD-1), chemotaxis marker (CXCR3), and tissue-resident markers (CD69 and CD103), along with increased expression of granzyme B and granulysin, compared to eCD8⁺T cells. In vitro cytotoxicity assays further demonstrated that dCD8⁺T cells had greater effector functions than eCD8⁺T cells. Additionally, both in vitro and in vivo chemotaxis assays confirmed the recruitment of non-resident effector memory T cell subsets to the pregnant decidua, contributing to the dCD8⁺T cell-mediated anti-infection mechanism at the maternal-fetal interface. This work demonstrates dCD8⁺T cells replenished from the circulation retain their cytotoxic capacity, which may serve as an enhanced defense mechanism against infection during pregnancy.

Despite the central role of cytokines in mediating inflammation that underlies a range of childhood diseases, cytokine testing remains primarily limited to research settings and surrogate markers of inflammation are often used to inform clinical diagnostic and treatment decisions. There are currently no reference ranges available for cytokines in healthy children, either systemically (in blood) or at sites of disease (such as the lung). In our study, we aimed to develop an openly accessible dataset of cytokines in the airways and blood of healthy children spanning 1 to 16 years of age. We examined how cytokine concentration changes during childhood and assessed whether a core set of cytokine markers could be used to indirectly evaluate the response of a broad spectrum of inflammatory analytes. To develop our dataset, a total of 65 unique analytes were quantified in cell-free bronchoalveolar lavage (BAL) and plasma from 78 children. We showed that age profoundly impacts soluble immune analyte concentration in both sample types and identified a highly correlative core set of 10 analytes in BAL and 11 analytes in plasma capable of indirectly evaluating the response of up to 44 inflammatory mediators. This study addresses an urgent need to develop reference ranges for cytokines in healthy children to aid in diagnosis of disease, to determine eligibility for, and to monitor the effects of, cytokine-targeted monoclonal antibody therapy.

We aimed to elucidate the dynamic changes in short-chain fatty acids (SCFA) produced by the gut microbiota following smoking exposure and their role in chronic obstructive pulmonary disease (COPD) pathogenesis. SCFA concentrations were measured in human plasma, comparing non-smokers (n = 6) and smokers (n = 12). Using a mouse COPD model induced by cigarette smoke exposure or elastase-induced emphysema, we modulated SCFA levels through dietary interventions and antibiotics to evaluate their effects on inflammation and alveolar destruction. Human smokers showed lower plasma SCFA concentrations than non-smokers, with plasma propionic acid positively correlating with forced expiratory volume in 1 s/forced vital capacity. Three-month smoking-exposed mice demonstrated altered gut microbiota and significantly reduced fecal SCFA concentrations compared to air-exposed controls. In these mice, a high-fiber diet increased fecal SCFAs and mitigated inflammation and alveolar destruction, while antibiotics decreased fecal SCFAs and exacerbated disease features. However, in the elastase-induced model, fecal SCFA concentration remained unchanged, and high-fiber diet or antibiotic interventions had no significant effect. These findings suggest that smoking exposure alters gut microbiota and SCFA production through its systemic effects. The anti-inflammatory properties of SCFAs may play a role in COPD pathogenesis, highlighting their potential as therapeutic targets.

The role of innate receptors in initiating the early inflammatory response to helminth larval stages in affected tissues during their life cycle within the host remains poorly understood. Given its pivotal role in detecting microbial elements and eliciting immune responses, exploring the NOD1 receptor could offer crucial insights into immune responses to parasitic infections. By using the larval ascariasis model, the acute model for early Ascaris sp. infection in humans, we report that NOD1 signaling markedly regulates pulmonary tissue inflammation during Ascaris larval migration. Here we show that Ascaris-infected NOD1-deficient mice exhibited a pronounced decrease in macrophage and eosinophil recruitment to the lungs. This diminished cellular recruitment to the lung correlated with impaired production of a mixed cytokine profile including IFN-γ, IL-1β, IL-5, IL-10, IL-17 and IL-33. The attenuated inflammatory response observed in the absence of NOD1 signaling during infection was associated with a notable amelioration in lung dysfunction compared to WT-infected mice. Systemically, NOD1 signaling was also associated with Ascaris-specific IgG2b antibody responses. In summary, our findings highlight a pathogenic role for NOD1 signaling in Ascaris-induced tissue inflammation, underlying hematopoietic cell recruitment and regulating downstream inflammatory cascades associated with the host's innate immune responses in the tissue triggered by helminth larval migration.

Recent evidence suggests that the gut microbiota can influence pain sensitivity, highlighting the potential for microbiota-targeted pain interventions. During early life, both the microbiota and nociceptors are fine-tuned and respond to environmental factors, however, little is known about how they interact with each other. Using germ-free and gnotobiotic models, we demonstrate that microbiota colonization controls nociceptor sensitivity, partly by modulating mast cell production of nerve growth factor (NGF). We report that germ-free mice respond less to thermal and capsaicin-induced stimulation, which correlates with reduced trafficking of TRPV1 to the cell membrane of nociceptors. In germ-free mice, mast cells express lower levels of NGF. Hyposensitivity to thermal and capsaicin-induced stimulation, reduced TRPV1 trafficking, and decreased NGF expression are reversed when mice are colonized at birth, but not when colonization occurs after weaning. Inhibition of mast cell degranulation and NGF signaling during the first weeks of life in colonized mice leads to a hyposensitive phenotype in adulthood, demonstrating a role for mast cells and NGF signaling in linking early life colonization with nociceptor sensitivity. These findings implicate the early life microbiota in shaping mast cell NGF production and nociceptor sensitivity later in life. SIGNIFICANCE STATEMENT: Nociceptors are specialized sensory neurons that detect and transduce painful stimuli. During the early postnatal period, nociceptors are influenced by sensory experiences and the environment. Our findings demonstrate that gut microbiota colonization is essential in setting the threshold of nociceptor responses to painful stimuli. We show that early-life bacterial colonization controls the production of nerve growth factor by mast cells, affecting our sensitivity to pain later in life. Our study highlights the potential for developing new pain treatments that target the gut microbiome.

Interleukin (IL)-33 is released following tissue damage, causing airway inflammation and remodelling via reduced IL-33 (IL-33^red)/serum stimulation-2 (ST2) and oxidised IL-33 (IL-33^ox)/receptor for advanced glycation end products (RAGE)/epidermal growth factor receptor (EGFR) pathways. This study aimed to identify associations of IL-33 with clinical outcomes and pathological mechanisms during viral lower respiratory tract disease (LRTD). Ultra-sensitive immunoassays were developed to measure IL-33^red, IL-33^ox and IL-33/sST2 complexes in samples from patients hospitalised with COVID-19. Immunohistochemistry and multiomics were used to characterise lung samples. Elevated IL-33 in the airway and IL-33/sST2 complex in the circulation correlated with poor clinical outcomes (death, need for intensive care or mechanical ventilation). IL-33 was localised to airway epithelial and endothelial barriers, whereas IL1RL1 was expressed on aerocytes, alveolar endothelial cells specialised for gaseous exchange. IL-33 increased expression of mediators of neutrophilic inflammation, immune cell infiltration, interferon signalling and coagulation in endothelial cell cultures. Endothelial IL-33 signatures were strongly related with signatures associated with viral LRTD. Increased IL-33 release following respiratory viral infections is associated with poor clinical outcomes and might contribute to alveolar dysfunction. Although this does not show a causal relationship with disease, these results provide a rationale to evaluate pathological roles for IL-33 in viral LRTD.