Journal of Innate Immunity最新文献

Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by dysregulated immune responses in the gut. Macrophages, as key innate immune cells in the intestinal mucosa, play a central role in both maintaining homeostasis and driving pathology in UC.

Summary: Under physiological conditions, intestinal macrophages exhibit a unique "inflammatory anergy" phenotype, supporting epithelial integrity and immune tolerance. In UC, however, persistent inflammatory signals promote monocyte recruitment and their polarization into pro-inflammatory M1-like macrophages. These cells secrete cytokines such as TNF-α, IL-1β, IL-6, and IL-12/23, produce reactive oxygen and nitrogen species (ROS/RNS), and release matrix metalloproteinases (MMPs), collectively driving epithelial barrier disruption, tissue damage, and sustained inflammation. This review comprehensively discusses the origin, heterogeneity, and functional plasticity of intestinal macrophages, their dynamic interactions with other cells, and key regulatory signaling pathways-such as NF-κB, JAK-STAT, and the NLRP3 inflammasome-in UC.

Key messages: We evaluate current and emerging macrophage-targeted therapies, including cytokine blockade, chemokine receptor antagonism, phenotypic reprogramming, nanomedicine, and cell-based interventions. Furthermore, we highlight the limitations of the M1/M2 dichotomy and emphasize the need for single-cell and spatial transcriptomic approaches to better define macrophage subsets in human disease. Advancing the understanding of macrophage biology in UC will facilitate the development of precise immunomodulatory strategies and biomarker-based diagnostics, ultimately aiming to bridge the gap between mechanistic discovery and improved patient care.

Introduction: Hemocytes are central to honey bee (Apis mellifera) immunity, but the roles of their subtypes under combined stressors are unclear. We tested the effects of temperature and bacterial challenge on hemocyte abundance and, for the first time in honey bees, used clodronate liposomes (CLD) to selectively deplete hemocytes.

Methods: Five-day-old (Nurses) and fifteen-day-old (Foragers) honey bees were treated with CLD, control liposomes, PBS, or left untreated, then exposed at either 32°C or 22°C and challenged with Escherichia coli, or Staphylococcus aureus. Survival, hemolymph volume, total hemocyte counts, and differential hemocyte counts were monitored over seven days.

Results: The CLD application demonstrated significant reductions in granulocyte and prohemocyte populations, indicating the highest vulnerability. A temperature drop to 22ºC buffered the negative impact on survival of CLD-induced immunosuppression. While bacterial challenges universally reduced hemocyte counts, we found a fundamental age-dependent difference where nurses maintained significantly higher baseline total hemocyte counts than foragers. Furthermore, temperature did not affect overall total hemocyte counts in 5-day-old nurse bees, but in 15-day-old foragers, it significantly modulated the hemocyte response to bacterial infection.

Conclusion: Hemocyte function is subtype-specific, shaped by temperature and age, with foragers showing greater vulnerability. Clodronate liposomes provide a new tool to dissect honey bee immune-environment interactions.

Introduction: Chloroquine (CQ), a well-known antimalarial agent, has been proposed as a potential antiviral compound due to its ability to interfere with multiple cellular pathways critical for viral replication. Although CQ exhibits broad-spectrum antiviral activity, its effect on host innate immune responses remains incompletely understood. The timing of CQ administration, whether before or after infection, may lead to different immunological outcomes. Therefore, the immunomodulatory effects of CQ should be carefully evaluated before antiviral therapy.

Methods: To investigate the immunomodulatory role of CQ (50 μm), we used immunofluorescence staining, Western blotting, and reporter assays to evaluate innate immune activation in A549 cells. We established a doxycycline-inducible system to activate mitochondrial antiviral signaling (MAVS)-mediated signaling without viral infection. Plaque assays and antiviral tests were performed to measure viral replication, while cytokine array and RT-qPCR were used to quantify cytokine production. Mitochondrial morphology was assessed using immunofluorescence microscopy.

Results: CQ enhanced innate immune responses triggered by dengue virus infection and poly(I:C) stimulation. This enhancement was associated with the activation of the MAVS protein and its upstream receptors, including retinoic acid-inducible gene I and melanoma differentiation-associated protein 5. CQ strengthened MAVS-dependent antiviral signaling and increased IL-6 induction more than 13-fold. Alterations in mitochondrial morphology may contribute to this immunostimulatory effect.

Conclusion: CQ promotes MAVS-mediated antiviral and inflammatory cytokine responses, potentially through its effect on mitochondrial dynamics. These findings indicate that while CQ may enhance antiviral defense, its immune-stimulating properties should be carefully evaluated prior to its use as an antiviral agent in treating RNA virus infections.

Background: Neutrophils, previously viewed as short-lived microbial killers, are now recognized as highly adaptable regulators of innate immunity. Advances in transcriptomic, metabolic, and epigenetic profiling reveal their remarkable heterogeneity and ability to adopt microenvironment-specific phenotypes. In the lung, this plasticity gives neutrophils a double role: they fight infection but can also cause long-lasting inflammation, tissue damage, and scarring.

Summary: We review how neutrophils are activated, move, and act in lung disease, focusing on their release of proteases, production of reactive oxygen species, and formation of extracellular traps. We also describe repair-promoting neutrophil types and treatments that aim to reduce damage while keeping normal neutrophil defense intact.

Key messages: Learning how neutrophils change within the lung microenvironment will help create better and more precise treatments for lung inflammation and tissue damage.

Repeated exposures to Mycobacterium tuberculosis (Mtb) and related species may influence host responses, which in turn may affect vaccine efficacy and could even render the host less or more susceptible to progression to active tuberculosis disease. Using well-differentiated primary human bronchial epithelial cells (PBEC), we investigated the effect of a prior exposure of the epithelium to Mtb and M. bovis (BCG) on the intracellular infection efficiency of Mtb and M. avium (Mav) during a second exposure, and measured cytokine and antimicrobial peptide secretion. PBEC that were first exposed to BCG were significantly more resistant to subsequent infection with Mtb. A similar trend was observed in PBEC that were previously exposed to Mtb, although to a lesser magnitude compared to BCG pre-exposure. Furthermore, while the first exposure to mycobacteria induced inflammatory cytokine secretion by PBEC, cytokine secretion was dampened upon a secondary exposure to Mtb, most strongly in previously BCG-exposed cells. Secretion of the antimicrobial peptide hBD-2 was not affected by sequential exposures. In conclusion, repeated exposure of differentiated airway epithelial cells to mycobacteria reduced intracellular infection and inflammation.

Introduction: Group B Streptococcus (GBS) asymptomatic colonizes the female genital tract (FGT) but can contribute to adverse pregnancy outcomes including pre-term birth, chorioamnionitis, and neonatal infection. We previously observed that GBS elicits FGT cytokine responses, including IL-17, during murine vaginal colonization; yet the anti-GBS cellular immune response during colonization remained unknown. We hypothesized that GBS may induce cellular immunity, resulting in FGT clearance.

Methods: Herein, we utilize depleting antibodies and knockout mice and performed flow cytometry to investigate cellular immunes responses during GBS colonization.

Results: We found that neutrophils (effectors of the IL-17 response) are important for GBS mucosal control as neutrophil depletion promoted increased GBS burdens in FGT tissues. Flow cytometric analysis of immune populations in the vagina, cervix, and uterus revealed, however, that GBS colonization did not induce a marked increase in FGT CD45+ immune cells. We also found that that Vγ6+ γδ T cells comprise a primary source of FGT IL-17. Finally, using knockout mice, we observed that IL-17-producing γδ T cells are important for the control of GBS in the FGT during murine colonization.

Conclusions: Taken together, this work characterizes FGT cellular immunity and suggests that GBS colonization does not elicit a significant immune response, which may be a bacterial directed adaptive outcome. However, certain FGT immune cells, such as neutrophils and ɣδ T cells, contribute to host defense and control of GBS colonization.

Respiratory system diseases, including infections, inflammation, fibrosis, cancer, and others, impose a substantial burden on human health worldwide. The respiratory tract is constantly exposed to external stimuli due to its connection with the outside environment. Therefore, the immune system plays a crucial role in respiratory diseases. Toll-like receptors (TLRs) recognize pathogens and initiate immune responses, serving as the first line of host defense against external pathogen invasion. Interleukin-1 receptor-associated kinases (IRAKs) are a group of kinases that mediate activation signals from TLRs and the interleukin-1 receptor (IL-1R). Among the four distinct IRAK family members, interleukin-1 receptor-associated kinase M (IRAK-M) uniquely functions as a pseudokinase and serves as a critical negative regulator of TLR/IL-1R signaling pathways, mediating diverse immunomodulatory effects in various pulmonary diseases. This review focuses on recent advancements in understanding the role of IRAK-M in lung disorders, aiming to provide a basis for future investigations into the pathogenesis and potential therapeutic targets for such conditions.

Abnormal immune responses are common clinical features in septic patients. γδ T cells, as innate immune cells, play an important role in host defense, immune surveillance and homeostasis. However, the immune characteristics of γδ T cells in pediatric sepsis remains remain poorly understood. In this study, we analyzed single-cell RNA high-throughput sequencing data of peripheral blood mononuclear cells (PBMCs) from pediatric septic patients. It demonstrates that γδ T cells exhibit a proinflammatory state with heightened immune responsiveness to pathogens in pediatric sepsis, as confirmed by the results of flow cytometric analysis showing elevated Th1 cytokines secretion, increased activation, and a propensity to differentiate into IL-17-producing (γδT17) cells during disease progression. Pseudotime analysis identified seven key genes potentially regulating the differentiation of γδ T cells to γδT17 subtype. Furthermore, cell-cell communication analysis revealed enhanced RETN-CAP1 binding between neutrophils and γδ T cells in pediatric sepsis, suggesting that neutrophil-derived resistin may promote γδ T cell differentiation into the γδT17 subtype via CAP1 receptor binding. In conclusion, this study provides a single-cell study that analyzed the immune status of γδ T cells in pediatric sepsis, highlighting their pivotal roles in pathogen response, inflammation propagation, and immune regulation. The observed differentiation toward the γδT17 subtype may facilitate neutrophil recruitment in this life-threatening condition. Elucidating the molecular mechanisms of γδ T cells in pediatric sepsis could offer a new theoretical basis for novel therapeutics.

Piezo-type mechanosensitive ion channel component 1 (Piezo1) is an evolutionarily conserved and multifunctional mechanosensitive ion channel protein that has emerged as a significant contributor to the pathogenesis of inflammatory bowel disease (IBD). Piezo1 plays a crucial role in regulating intestinal barrier integrity, immune responses, and the intestinal nervous system, thereby influencing disease progression. Its expression patterns correlate with disease severity and inflammatory markers in IBD patients, indicating its potential as a diagnostic and prognostic biomarker. Mechanistically, Piezo1 activation modulates key signaling pathways involved in IBD, including NF-κB, ROCK, mTOR, and 5-HT signaling pathways. Targeting Piezo1, either by modulating its expression or function, represents a promising therapeutic strategy for IBD. This review summarizes the current understanding of Piezo1's structure, biological functions, mechanisms of action, and clinical implications in the context of IBD, providing insights into its potential as a therapeutic target and biomarker for this chronic gastrointestinal disorder.