Mucosal Immunology最新文献

Intestinal immune homeostasis relies on intestinal epithelial cells (IECs), which provide an efficient barrier, and warrant a state of tolerance between the microbiome and the mucosal immune system. Thus, proper epithelial microbial sensing and handling of microbes is key to preventing excessive immunity, such as seen in patients with inflammatory bowel disease (IBD). To date, the molecular underpinnings of these processes remain incompletely understood. This study identifies TIFA as a driver of intestinal inflammation and an epithelial signaling hub between the microbiome and mucosal immune cells. TIFA was constitutively expressed in crypt epithelial cells and was highly induced in the intestine of mice and IBD patients with intestinal inflammation. We further identified IL-22 signaling via STAT3 as key mechanism driving TIFA expression in IECs. At the molecular level, we demonstrate that TIFA expression is essential for IEC responsiveness to the bacterial metabolite ADP-heptose. Most importantly, ADP-heptose-induced TIFA signaling orchestrates an inflammatory cellular response in the epithelium, with NF-κB and inflammasome activation, and high levels of chemokine production. Finally, mice lacking TIFA were protected from intestinal inflammation when subjected to a model of experimental colitis. In conclusion, our study implicates that targeting TIFA may be a strategy for future IBD therapy.

First- and secondhand smokers are at an increased risk for influenza virus (IFV)-related respiratory failure and death. Despite approved influenza antiviral treatments, there is an unmet need for treatments that can improve outcomes in populations at risk for respiratory failure, including tobacco users with Chronic Obstructive Pulmonary Disease (COPD). Here we show that the sialidase fusion protein, DAS181, reduced viral burden, mitigated inflammation, and attenuated lung function loss, consistent with broad-spectrum anti-influenza responses in a mouse model of COPD and IFV-A infection. Treatment with DAS181 reprogramed the sialic acid-binding immunoglobulin-like lectins (Siglecs) in alveolar macrophages, increased expression of phagocytic marker CD169, and downregulated inhibitory Siglec-F and Siglec-H molecules. Upon reinfection, mice treated with DAS181 showed activated and protective memory response in the lungs. Collectively, we show that this sialidase fusion protein promotes a beneficial immunomodulatory reaction in the lungs, supporting a new IFV-A therapeutic option for at-risk smokers.

Immunoglobulin A (IgA), the most abundantly produced antibody at mucosal surfaces, is thought to play key roles in immune responses to respiratory and enteric pathogens and in the regulation of commensal colonization. Low IgA levels have been associated with recurrent infections and immune dysregulation, including inflammatory bowel disease and autoimmunity. Levels of IgA in maternal breast milk and infant stool are both inversely associated with the emergence of immune responses to food antigens in infants and, in naturally resolving food sensitivity and immunotherapy protocols, the induction of IgA antibodies to dietary antigens has been associated with the acquisition of food tolerance. Here, we uncover new roles for IgA in intestinal immune homeostasis utilizing IgA Knockout (KO) mice generated by CRISPR/Cas9. IgA-deficient mice exhibit hyperimmunoglobulinemia, with increased levels of IgE and MCPT-1. The hyperimmunoglobulinemia is associated with dysregulated Tfh/Tfr responses in the Peyer's Patches (PPs) and spontaneous immunoglobulin production to chow diet. These findings shed light on important interactions between IgA, the mucosal immune system, and the regulation of Tfh responses, emphasizing the importance of IgA in maintaining immune homeostasis at mucosal surfaces.

Mucosal tissues, including those in the respiratory and gastrointestinal tracts, are critical barrier surfaces for pathogen invasion. Infections at these sites not only trigger local immune response, but also recruit immune cells from other tissues. Emerging evidence in the mouse models and human samples indicates that the immune crosstalk between the lung and gut critically impacts and determines the course of respiratory disease. Here we summarize the current knowledge of the immune crosstalk between the respiratory and gastrointestinal tracts, and discuss how immune cells are recruited and migrate between these tissues during respiratory infections. We also discuss how commensal bacteria contribute to these processes.

Diabetes mellitus is associated with an increased risk of pneumonia, often caused by so-called typical and atypical pathogens including Streptoccocus pneumoniae and Legionella pneumophila, respectively. Here, we employed a variety of mouse models to investigate how diabetes influences pulmonary antibacterial immunity. Following intranasal infection with S. pneumoniae or L. pneumophila, type 2 diabetic and prediabetic mice exhibited higher bacterial loads in their lungs compared to control animals. Single cell RNA sequencing, flow cytometry, and functional analyses revealed a compromised IFNγ production by natural killer cells in diabetic and prediabetic mice, which was associated with reduced IL-12 production by CD103⁺ dendritic cells. Blocking IFNγ enhanced susceptibility of non-diabetic mice to L. pneumophila, while IFNγ treatment restored defense against this intracellular pathogen in diabetic animals. In contrast, IFNγ treatment did not increase resistance of diabetic mice to S. pneumoniae, suggesting that impaired IFNγ production is not the sole mechanism underlying the heightened susceptibility of these animals to pneumococcal infection. Thus, our findings uncover a mechanism that could help to explain how type 2 diabetes predisposes to pneumonia. We establish proof of concept for host-directed treatment strategies to reinforce compromised IFNγ-mediated antibacterial defense against atypical lung pathogens.

Inflammatory bowel diseases (IBDs) are characterized by unrestrained innate and adaptive immune responses and compromised intestinal epithelial barrier integrity. Regulatory T (T_reg) cells are crucial for maintaining self-tolerance and immune homeostasis in intestinal tissues. Prostaglandin E₂ (PGE₂), a bioactive lipid compound derived from arachidonic acid, can modulate T cell functions in a receptor subtype-specific manner. However, whether PGE₂ regulates T_reg cell function and contributes to IBD pathogenesis remains unclear. Here, we found that the PGE₂ receptor subtype 2 (EP2) is highly expressed in T_reg cells. T_reg cell-specific deletion of EP2 resulted in increased T_reg cell numbers, and enhanced granzyme B(GzmB) expression and immunosuppressive capacity of T_reg cells in mice. Adoptive transfer of EP2-deficient T_reg cells attenuated naïve CD4⁺ T cell transfer-induced colitis in Rag1^-/- mice. Mice with EP2-deficient T_reg cells were protected from 2,4,6-trinitrobenzene sulfonic acid (TNBS)- and dextran sodium sulfate (DSS)-induced colitis. Pharmacological blockage of EP2 with PF-04418948 markedly alleviated DSS-induced colitis in mice in a T_reg-dependent manner. Mechanistically, activation of EP2 suppressed T_reg cell function, at least in part, through reduction of GzmB expression via PKA-mediated inhibition of NF-κB signaling. Thus, we identified the PGE₂/EP2 axis as a key negative modulator of T_reg cell function, suggesting EP2 inhibition as a potential therapeutic strategy for IBD treatment.

Neuro-immune interactions within barrier organs, such as lung, gut, and skin, are crucial in regulating tissue homeostasis, inflammatory responses, and host defence. Our rapidly advancing understanding of peripheral neuroimmunology is transforming the field of barrier tissue immunology, offering a fresh perspective for developing therapies for complex chronic inflammatory disorders affecting barrier organs. However, most studies have primarily examined interactions between the peripheral nervous system and the immune system from a neuron-focused perspective, while glial cells, the nonneuronal cells of the nervous system, have received less attention. Glial cells were long considered as mere bystanders, only supporting their neuronal neighbours, but recent discoveries mainly on enteric glial cells in the intestine have implicated these cells in immune-regulation and inflammatory disease pathogenesis. In this review, we will highlight the bi-directional interactions between peripheral glial cells and the immune system and discuss the emerging immune regulatory functions of glial cells in barrier organs.

The precise role of neutrophil-derived reactive oxygen species (ROS) in combating bacterial uropathogens during urinary tract infections (UTI) remains largely unexplored. In this study, we elucidate the antimicrobial significance of NADPH oxidase 2 (NOX2)-derived ROS, as opposed to mitochondrial ROS, in facilitating neutrophil-mediated eradication of uropathogenic Escherichia coli (UPEC), the primary causative agent of UTI. Furthermore, NOX2-derived ROS regulate NF-κB-mediated inflammatory responses in neutrophils against UPEC by inducing the release of nuclear factor erythroid 2-related factor 2 (Nrf2) from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1). Consistently, the absence of NOX2 (Cybb^-/-) in mice led to uncontrolled bacterial infection associated with increased NF-κB signaling, heightened neutrophilic inflammation, and increased bladder pathology during cystitis. These findings underscore a dual role for neutrophil NOX2 in both eradicating UPEC and mitigating neutrophil-mediated inflammation in the urinary tract, revealing a previously unrecognized effector and regulatory mechanism in the control of UTI.

The murine uterus contains three subsets of innate lymphoid cells (ILCs). Innate lymphoid cell type 1 (ILC1) and conventional natural killer (cNK) cells seed the uterus before puberty. Tissue-resident NK (trNK) cells emerge at puberty and vary in number during the estrous cycle. Here, we addressed the origin of uterine trNK cells and the influence of ovarian hormones on their local activation and differentiation in vivo. We used parabiosed mice in combination with intravascular fluorescent antibody labeling and flow cytometry to distinguish tissue-resident from circulating immune cells. Additionally, we used C57BL/6J ovariectomized (OVX) and non-OVX mice supplemented with ovarian hormones to assess their effects on uterine trNK cell function. Strikingly, mice OVX at three weeks of age and analyzed as adults lacked uterine trNK cells unless progesterone was administered. Our parabiosis studies confirmed that the progesterone-responsive trNK cells are derived from peripheral cNK cells. Moreover, medroxyprogesterone 17-acetate-induced expansion of cNK-derived trNK cells was abolished by a progesterone receptor antagonist. These data reveal a novel, uterine-specific differentiation pathway of trNK cells that is tightly regulated by progesterone.