Regulation Of Immune Responses Research Articles

Chromosome-Level Genome Assembly and Comparative Genomic Analysis of Planiliza haematocheilus: Insights into Environmental Adaptation and Hypoxia Tolerance Mechanisms.

Planiliza haematocheilus, a teleostan species noted for its ecological adaptability and economic significance, thrives in both freshwater and marine environments. This study presents a novel chromosome-level genome assembly through Hi-C, PacBio CCS, and Illumina sequencing methods. The assembled genome has a final size of 651.58Mb, with 24 chromosomes anchoring 91.94% of contigs. Contig N50 and scaffold N50 are respectively measured at 25.52Mb and 28.59Mb. Of the 22,476 protein-coding genes identified in the genome, 21,834 have functional annotations. BUSCO (Benchmarking Universal Single-Copy Orthologs) genome and gene annotation assessments yielded scores of 96% and 96.6%, respectively. The genome of P. haematocheilus revealed 228 expanded and 1433 contracted gene families. Comparative genomic analyses highlight adaptations and hypoxia tolerance, linked to protein synthesis, immune response, and metabolic regulation. The high-quality genome assembly supports advanced studies on gene expression patterns under different environmental stressors, contributing to genetic enhancement efforts for this economically important aquaculture species.

Inhibiting NLRP3 enhances cellular autophagy induced by outer membrane vesicles from Pseudomonas aeruginosa.

The bacterium Pseudomonas aeruginosa is able to invade lung epithelial cells and survive intracellularly. During this process, it secretes outer membrane vesicles (OMVs), however, it is currently unclear how OMVs from P. aeruginosa (PA-OMVs) affect lung epithelial cells and their impact on oxidative stress, autophagy, and other physiological activities of lung epithelial cells. In this study, we found that PA-OMVs activated oxidative stress and autophagy in cells. We demonstrated that the NLRP3 (NLR family, pyrin domain containing 3) inhibitor MCC950 can enhance autophagy induced by PA-OMVs. The main function of NLRP3 is related to the body's immune response and inflammation regulation. MCC950 is the most common inhibitor of NLRP3. Additionally, we showed that PA-OMVs not only enhanced the expression of AMP-activated protein kinase, a key regulator of cellular energy homeostasis, and reactive oxygen species, which play a crucial role in cellular signaling and oxidative stress, but also significantly enhanced the expression of NLRP3. Inhibiting the expression of NLRP3 further enhanced the process of PA-OMVs induced autophagy. These results demonstrate that PA-OMVs activate both autophagy and the NLRP3 inflammasome, with NLRP3 suppressing autophagy to a certain extent, hoping to provide broad ideas for the future applications of PA-OMVs.IMPORTANCEThe discovery that lung epithelial cells exposed to outer membrane vesicles from Pseudomonas aeruginosa (PA-OMVs) activate cellular autophagy and induce protective immunity is significant. Specifically, the addition of an NLRP3 inhibitor, MCC950, has been found to decrease NLRP3 targets while simultaneously enhancing the autophagy activity induced by PA-OMVs. This finding unveils a novel theoretical framework for the development of PA-OMVs vaccines, highlighting new targets for enhancing the body's anti-infective responses. By elucidating the mechanisms through which PA-OMVs trigger autophagy and bolster immune defenses, this research opens avenues for innovative vaccine design strategies aimed at combatting infections effectively.

Integration of Mendelian Randomization to explore the genetic influences of pediatric sepsis: a focus on RGL4, ATP9A, MAP3K7CL, and DDX11L2

ObjectiveThis study aims to explore the genetic characteristics of pediatric sepsis through a combined analysis of multiple methods, including Mendelian Randomization (MR), differential gene expression analysis, and immune cell infiltration assessment. It explores their potential as biomarkers for sepsis risk and their involvement in immune-related pathways.MethodsDifferential expression analysis was performed using public datasets to identify genes with significant expression changes between pediatric sepsis patients and healthy controls. MR analysis utilized genome-wide significant SNPs as instrumental variables to assess causal relationships between gene expression and sepsis risk. Bi-directional MR was conducted to assess both forward and reverse causality. FDR correction was applied to adjust for multiple comparisons in MR results. Immune cell infiltration analysis was performed to investigate the genes’ roles in immune responses, and findings were validated with independent datasets. ROC curves were constructed to assess predictive performance.ResultsDifferential expression analysis identified significant changes in RGL4,ATP9A,MAP3K7CL, and DDX11L2. MR analysis revealed causal associations between these genes and sepsis risk, with RGL4 and ATP9A upregulated (inflammatory roles), and MAP3K7CL and DDX11L2 downregulated (protective roles). Bi-directional MR found no significant reverse causality. Immune cell analysis showed associations with key immune cell types, and ROC analysis demonstrated strong predictive potential.ConclusionRGL4,ATP9A,MAP3K7CL, and DDX11L2 play important roles in pediatric sepsis risk and immune response regulation, offering insights into genetic and immune mechanisms that may inform future sepsis research and treatment.

Role of Crosstalk Between Gut Microbiota and Immune Cells in Colorectal Cancer: A Narrative Review

Abstract Colorectal cancer (CRC) ranks among the most prevalent and deadly cancers globally, with its incidence increasing due to lifestyle factors such as increased consumption of red meat and decreased vegetable intake. A distinctive aspect of CRC is its strong connection to the gut microbiota, which is crucial in both tumorigenesis and immune regulation. This narrative review provides a comprehensive analysis of the interactions between gut microbiota and the immune system, focusing on their importance in CRC progression and responses to immunotherapy. Imbalances in the composition of gut microbes are strongly associated with CRC development. Notably, species such as Fusobacterium nucleatum and Bacteroides fragilis have been identified as key regulators of immune responses within the tumor microenvironment. These microbes affect the functions of immune cells, such as T cells, macrophages and myeloid-derived suppressor cells, thereby influencing cancer progression and prognosis. Additionally, this review underscores the potential of gut microbiota as biomarkers for CRC detection and outcome prediction. There is also growing interest in the use of probiotics, fecal microbiota transplantation and dietary modifications as supplementary treatments. A deeper understanding of how microbial communities interact with the immune system may pave the way for novel personalized therapies, particularly by enhancing the effectiveness of immune checkpoint inhibitors.

In vivo CRISPR screening identifies tada2b as a key epigenetic regulator of immune response in adrenocortical carcinoma

<i>In vivo</i> CRISPR screening identifies tada2b as a key epigenetic regulator of immune response in adrenocortical carcinoma

Targeting Nanotherapeutics for Highly Efficient Diagnosis and Treatment of Systemic Lupus Erythematosus through Regulation of Immune Response

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies, particularly antidouble‐stranded (ds) DNA antibodies, which contribute to multiorgan damage (lupus nephritis, LN). Hence, there is an urgent need to recognize and eliminate SLE‐specific anti‐ds DNA antibodies to enhance the SLE treatment. Herein, mesoporous silica (MSNs) loaded with SeC and surface‐modified ctDNA are constructed to effectively specific bind and eliminate pathogenic anti‐dsDNA antibodies for treatment SLE in 125 plasm and enabling swift LN diagnosis in 36 kidney tissue from SLE patients. As expected, the clearance ratio of anti‐dsDNA antibodies by nanotherapeutics is significantly greater compared to other products commonly used in clinical therapies and exhibits biocompatibility and safety in patients. Moreover, MSNs‐DNA can also help visualize the distribution of anti‐dsDNA antibodies in the lesions of the kidney. Importantly, the combination strategy (MSNs‐DNA@SeC) can effectively remove antibodies and reduce UP production by the regulation of B cells and T cells in female MRL/lpr SLE model mice to alleviate related symptoms. Collectively, the resultant data not only presents a straightforward method for the systematic design of nanomedicine targeting SLE to enhance the effects on diagnosis and treatment, but also elucidates the potential mechanisms involving anti‐dsDNA antibodies in the pathogenesis and progression of SLE.

Advancements in drug discovery: integrating CADD tools and drug repurposing for PD-1/PD-L1 axis inhibition.

Despite significant strides in improving cancer survival rates, the global cancer burden remains substantial, with an anticipated rise in new cases. Immune checkpoints, key regulators of immune responses, play a crucial role in cancer evasion mechanisms. The discovery of immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 has revolutionized cancer treatment, with monoclonal antibodies (mAbs) becoming widely prescribed. However, challenges with current mAb ICIs, such as limited oral bioavailability, adverse effects, and high costs, underscore the need to explore alternative small-molecule inhibitors. In this work, we aimed to identify new potential ICI among all FDA-approved drugs. We employed QSAR models to predict PD-1/PD-L1 inhibition, utilizing a diverse dataset of 29 197 molecules sourced from ChEMBL, PubChem, and recent literature. Machine learning techniques, including Random Forest, Support Vector Machine, and Convolutional Neural Network, were employed for benchmarking to assess model performance. Additionally, we undertook a drug repurposing strategy, leveraging the best in silico model for a virtual screening campaign involving 1576 off-patent approved drugs. Only two virtual screening hits were proposed based on the criteria established for this approach, including: (1) QSAR probability of being active against PD-L1; (2) QSAR applicability domain; (3) prediction of the affinity between the PD-L1 and ligands through molecular docking. One of the proposed hits was sonidegib, an anticancer drug, featuring a biphenyl system. Sonidegib was subsequently validated for in vitro PD-1/PD-L1 binding modulation using ELISA and flow cytometry. This integrated approach, which combines computer-aided drug design (CADD) tools, QSAR modelling, drug repurposing, and molecular docking, offers a pioneering strategy to expedite drug discovery for PD-1/PD-L1 axis inhibition. The findings underscore the potential to identify a wider range small molecules to contribute to the ongoing efforts to advancing cancer immunotherapy.

P0095 Human multi-lineage gut-on-chip to study near-physiological epithelial barrier function and directed secretion

Abstract Background The human intestinal epithelium is composed of diverse cell types, enabling it to fulfil essential digestive functions such as absorption and secretion, while simultaneously acting as an immune interface. This epithelial barrier safeguards underlying immune cells in the lamina propria from luminal antigens by maintaining a mucus layer rich in antimicrobial peptides, preventing unwanted immune responses and allowing regulated cytokine and chemokine gradients. Despite advances in single-cell transcriptomics, understanding specific epithelial cell secretions remains limited. Methods To address this, we developed a human intestinal organ-on-chip (OoC) model, derived from human colon organoids, capable of forming a heterogenous, functional epithelial barrier without permeable supports. This OoC model provides concurrent access to luminal and basal compartments, allowing for mid- to high-throughput screenings, overcoming limitations of conventional transwell or 3D organoid cultures. Results In our study, we analysed barrier function by measuring transepithelial electrical resistance (TEER) and permeability as well as confirming tight junction assemble marked by ZO-1 and occludin. Cell type composition was modulated using distinct culture media, resulting in a heterogeneous cell composition including goblet cells, colonocytes, and enteroendocrine cells along with the proliferative compartment, evidenced by transcriptomic and protein analyses. Cytokine and chemokine secretions, notably CCL2, CCL20, IL-8, IL-18, and CXCL10, demonstrated cell type-dependent and spatially directed patterns, suggesting location-specific secretion along the crypt-surface axis in vivo. Under basal and stimulated conditions, our model retained responsiveness to bacterial stimuli, gluten-derived antigens, and pro-inflammatory conditions, confirming the important role of epithelial cells in immune response regulation. Conclusion Collectively, this OoC model offers a physiologically relevant platform for exploring human intestinal barrier function and epithelial-immune communication. This scalable, multi-lineage in vitro model advances our capacity to study directed secretion, barrier integrity, and epithelial cell type dependent immune response, supporting applications in disease modelling and personalized medicine development.

RAGE-mediated intestinal pro-inflammatory responses triggered by Giardia duodenalis.

Giardia duodenalis is a waterborne zoonotic protozoan that causes gastrointestinal inflammation. Giardiasis and metabolic illnesses share features such as chronic inflammation and intestinal symptoms. Receptor for advanced glycation end products (RAGE) signaling plays a role in metabolic illnesses and intestinal inflammatory responses. The presence of protozoan viruses can influence host immunological responses triggered by protozoa. However, these effects of G. duodenalis remain unknown. In this study, mice treated with the RAGE inhibitor FPS-ZM1 showed more severe intestinal damage, including increased intestinal permeability and lesions, compared to that of the untreated group. Next, we found that G. duodenalis infection activated RAGE, leading to increased secretion of pro-inflammatory cytokines, including IL-1 β, IL-6, IL-12, TNF-α and IFN-γ in mouse intestinal epithelial cells. Notably, these pro-inflammatory responses were significantly higher in Giardiavirus (GLV)-free Giardia than those of GLV-containing Giardia, except for IFN-γ. Additionally, lactate dehydrogenase (LDH) release, GSDMD-N cleavage, and the morphological observation of pyroptosis were significantly higher in cells induced by GLV-free Giardia than those infected with GLV-carrying Giardia. Differences were also observed in the MAPK (p-JNK, p-38, p-ERK) and NF-κB pathway activation, as well as reactive oxygen species (ROS) levels, with higher activation in cells infected by GLV-free Giardia, and the ROS was involved in the regulation of p38 MAPK and JNK activation. These findings reveal the potential of RAGE as a target for developing vaccines or drugs, suggesting the differences in the regulation of host immune responses induced by GLV-free Giardia or GLV-containing Giardia, providing new insights for the prevention and treatment of Giardia.

Uncovering the chromatin-mediated transcriptional regulatory network governing cold stress responses in fish immune cells.

Temperature fluctuations challenge ectothermic species, particularly tropical fish dependent on external temperatures for physiological regulation. However, the molecular mechanisms through which low-temperature stress impacts immune responses in these species, especially in relation to chromatin accessibility and epigenetic regulation, remain poorly understood. In this study, we investigate chromatin and transcriptional changes in the head kidney and thymus tissues of Nile tilapia (Oreochromis niloticus), a tropical fish of significant economic importance, under cold stress. By analyzing cis-regulatory elements in open chromatin regions and their associated transcription factors (TFs), we construct a comprehensive transcriptional regulatory network (TRN) governing immune responses, including DNA damage-induced apoptosis. Our analysis identifies 119 TFs within the TRN, with Stat1 emerging as a central hub exhibiting distinct binding dynamics under cold stress, as revealed by footprint analysis. Overexpression of Stat1 in immune cells leads to apoptosis and increases the expression of apoptosis-related genes, many of which contain Stat1 binding sites in their regulatory regions, emphasizing its critical role in immune cell survival during cold stress. These results provide insights into the transcriptional and epigenetic regulation of immune responses to cold stress in tilapia and highlight Stat1 as a promising target for enhancing cold tolerance in tropical fish species.

Trichinella spiralis extracellular vesicles induce anti-inflammatory and regulatory immune responses in vitro.

The helminth Trichinella spiralis, through its excretory-secretory (ES L1) products, induces immune regulatory mechanisms that modulate the host's immune response not only to itself, but also to bystander antigens, foreign or self in origin, which can result in the alleviation of inflammatory diseases. Under the influence of ES L1, dendritic cells (DCs) acquire a tolerogenic phenotype and the capacity to induce Th2 and regulatory responses. Since ES L1 products represent a complex mixture of proteins and extracellular vesicles (TsEVs) the aim of this study was to investigate the impact of TsEVs, isolated from ES L1 products, on phenotypic and functional characteristics of DCs and to elucidate whether TsEVs could reproduce the immunomodulatory effects of the complete ES L1 product. Monocyte-derived DCs treated with TsEVs acquired semi-matured phenotypes, characterized by low expression of human leukocyte antigen - DR isotype (HLA-DR), cluster of differentiation (CD) 86 (CD86), and CD40, moderate expression of CD83 and C-C chemokine receptor type 7 (CCR7), and increased expression of tolerogenic markers indoleamine 2,3-dioxygenase 1 (IDO-1) and immunoglobulin-like transcript 3 (ILT3), together with the unchanged production of IL-12 and IL-23, and elevated production of IL-10 and transforming growth factor (TGF)-β, compared with controls. Gene expression analysis of TsEV-treated DCs revealed elevated levels of mTOR, Ahr, NF-κB2, RelB, SOCS1 and SOCS3, which participate in signaling pathways involved in DC maturation and the subsequent regulation of release of both anti-inflammatory and pro-inflammatory cytokines. TsEVs promoted the capacity of DCs to drive polarization of Th2 and anti-inflammatory responses, and impaired their capacity to induce Th1/Th17 polarization. Moreover, TsEV-treated DCs possessed a high capacity to induce conventional FoxP3+ regulatory T cells, as well as unconventional T regulatory (Tr1) cells. Tolerogenic properties of TsEV-treated DCs were retained even after challenge with a pro-inflammatory stimulus. These findings highlight the potential of TsEVs to induce immune tolerance, suggesting their potential use as therapeutics for the treatment of inflammatory disorders.

NLRC3 Attenuates Antiviral Innate Immune Response by Targeting IRF7 in Grass Carp (Ctenopharyngodon idelus).

NLRC3 belongs to the NOD-like receptor family and is recognized as a modulator of innate immune mechanisms. In this study, we firstly report that Ctenopharyngodon idelus NLRC3 (CiNLRC3) acts as a negative regulator in the antiviral immune response. Cinlrc3 is ubiquitously expressed across tested tissues, displaying particularly high expression in the intestine, spleen, gill and kidney. Notably, Cinlrc3 expression is markedly upregulated following grass carp reovirus (GCRV) infection both in vivo and in vitro. Functional assays reveal that the overexpression of CiNLRC3 hampers cellular antiviral responses, thereby facilitating viral replication. Conversely, the silencing of CiNLRC3 through siRNA transfection enhances these antiviral activities. Additionally, CiNLRC3 substantially diminishes the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-mediated interferon (IFN) response in fish. Subsequent molecular investigations indicates that CiNLRC3 interacts with the RLR molecule node, IRF7 but not IRF3, by degrading the IRF7 protein in a proteasome-dependent manner. Furthermore, CiNLRC3 co-localizes with CiIRF7 in the cytoplasm and impedes the IRF7-induced IFN response, resulting in impairing IRF7-mediated antiviral immunity. Summarily, these findings underscore the critical inhibitory role of teleost NLRC3 in innate immunity, offering new perspectives on its regulatory functions and potential as a target for resistant breeding in fish.

Biochemistry and Clinical Significance of Il-3: A Review Article

Interleukin-3 (IL-3) is a cytokine of many activities, centrally important for hematopoiesis and regulation of immune responses. It is produced by activated T cells and mast cells with a large influence on blood cell lineage proliferation and differentiation. Given the biochemistry of IL-3, elucidating its role in health and disease—especially immune responses and pathological conditions—is a high priority. Interleukin-3 is a cytokine profoundly important in the regulation of hematopoiesis and immune responses. The ability of this factor to modulate a wide variety of cellular responses serves to underscore its central involvement in almost all physiological as well as pathological processes. In the present article, the authors summarize recent knowledge on the mechanisms by which IL-3 exerts biological effects, with special emphasis placed on receptor signaling, downstream pathways, and functional responses.

Role of Acorus calamus extract in reducing exosome secretion by targeting Rab27a and nSMase2: a therapeutic approach for breast cancer.

Exosomes are extracellular vesicles released by cells that mediate intercellular communication and actively participate in cancer progression, metastasis, and regulation of immune response within the tumour microenvironment. Inhibiting exosome release from cancer cells could be employed as a therapeutic against cancer. In the present study, we have studied the effects of Acorus calamus in inhibiting exosome secretion via targetting Rab27a and neutral sphingomyelinase 2 (nSMase2) in HER2-positive (MDA-MB-453), hormone receptor-positive (MCF-7) and triple-negative breast cancer (MDA-MB-231) cells. We observed that treatment with A. calamus significantly downregulated the expression of Rab27a and nSMase2 in all tested cells. NTA analysis showed that inhibition of Rab27a and nSMase2 reduced exosome secretion from breast cancer cells. We conducted metabolic profiling of A. calamus extract to reveal the phytochemicals present and docked them on Rab27a and nSMase2 to decipher the compounds responsible for protein inhibition. Molecular dynamic simulations were conducted on lead compounds, and we observed that calcitriol lactone showed the most stable binding interactions with nSMase2. Treatment of breast cancer cells with calcitriol lactone significantly downregulated nSMase2 expression. Our study demonstrates that A. calamus significantly inhibits exosome secretion in HER2-positive, hormone receptor-positive, and triple-negative breast cancer cells by targeting key regulatory proteins Rab27a and neutral sphingomyelinase 2 (nSMase2). These findings suggest that A. calamus holds therapeutic potential in inhibiting exosome-mediated cancer progression by targeting the exosome secretion pathway. Further investigations are warranted to explore the clinical applications of these findings in breast cancer treatment.

Genetic Risk Profiling Reveals Altered Glycosyltransferase Expression as a Predictor for Patient Outcome in Neuroblastoma.

Background/Objectives: Neuroblastoma is a highly aggressive pediatric cancer that arises from immature nerve cells and exhibits a broad spectrum of clinical presentations. While low- and intermediate-risk neuroblastomas often have favorable outcomes, high-risk neuroblastomas are associated with poor prognosis and significant treatment challenges. The complex genetic networks driving these high-risk cases remain poorly understood. This study aims to investigate differences in gene expression patterns that may contribute to disease outcomes. Methods: We employed an in silico approach to analyze a cohort of 493 neuroblastoma tumor samples that underwent mRNA sequencing (GSE49711). This dataset was reanalyzed in depth with a non-hypothesis-driven approach to identify the expression patterns and regulatory mechanisms associated with a poor prognosis. Results: By exploring global gene expression and the integration of clinical parameters, we stratified the samples into two groups with highly distinct gene expression profiles. MYCN amplification emerged as a major driver not only of poor prognosis but also of specific gene regulatory patterns. Notably, tumors with MYCN amplification exhibited the strong regulation of immune response genes and less immune infiltration, suggesting potential immune evasion. However, while we observed only minor changes in immune checkpoint expression, there was a strong modulation of glycosyltransferase genes in MYCN-amplified tumors. Using this information, we were able to construct a risk profile based on 12 glycosylation-related genes, which correlates with the survival outcomes of neuroblastoma patients. Conclusions: This study highlights the role of MYCN amplification in driving a poor prognosis in neuroblastoma through the regulation of immune response and glycosylation-related genes. Based on this finding, we developed a genetic risk profile that correlates with survival outcomes in neuroblastoma patients.

Long Non-Coding RNA LOC113219358 Regulates Immune Responses in Apis mellifera Through Protein Interactions.

Long non-coding RNAs (lncRNAs) are emerging as critical regulators in honeybee physiology, influencing development, behavior, and stress responses. This study investigates the role of lncRNA LOC113219358 in the immune response and neurophysiological regulation of Apis mellifera brains. Using RNA interference (RNAi) and RNA sequencing (RNA-seq), we demonstrate that silencing lncLOC113219358 significantly alters the expression of 162 mRNA transcripts, including genes associated with detoxification, energy metabolism, and neuronal signaling. Functional enrichment analysis revealed involvement in neuropeptide signaling, ATP synthesis, and oxidative phosphorylation pathways. Acetylcholinesterase (AChE), Glutathione-S-transferase (GST) and cytochrome P450 (CYP450) activities were significantly downregulated with 48 h of RNAi treatment. Additionally, RNA pull-down assays identified 113 proteins interacting with lncLOC113219358, including ATP synthase subunits, heat shock proteins, and major royal jelly proteins, suggesting its role in cellular stress responses and neural activity modulation. These findings provide mechanistic insights into how lncLOC113219358 mediates honeybee responses to environmental stressors, contributing to our understanding of lncRNA-regulated neural and immune functions in pollinators.

Specialized pro-resolving lipid mediators in gut immunophysiology: from dietary precursors to inflammation resolution.

This review aims to examine recent research on the role of specialized pro-resolving mediators (SPMs) in the regulation of gut immunophysiology. Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract, driven by disruptions in the intestinal barrier and an imbalance between the host immune system and gut microbiota. Dietary polyunsaturated fatty acids (PUFAs), especially ω-3 and ω-6, are key regulators of immune responses and help maintain the integrity of the intestinal barrier. These PUFAs serve as precursors to SPMs, lipid mediators that play a critical role in resolving inflammation. SPMs actively reprogram immune cells, promoting the clearance of cellular debris, reducing cytokine production, and restoring tissue homeostasis without suppressing the immune response. Emerging evidence indicates that in the gut, SPMs strengthen intestinal barrier function, modulate immune responses in colitis and colon cancer, and influence gut microbiota composition. The recent evidence strongly supports the central role of SPMs in maintaining gut health and restoring organ function following inflammatory challenges. This evidence highlights the potential of therapeutic approaches that target these pathways for both the prevention and treatment of gut-related inflammatory conditions.

YTHDF1-mediated m6A modification of GBP4 promotes M1 macrophage polarization in acute lung injury

BackgroundAcute lung injury (ALI) is a severe condition with multifaceted causes, including inflammation and oxidative stress. This research investigates the influence of m6A (N6-methyladenosine) modification on GBP4, a protein pivotal for macrophage polarization, a critical immune response in ALI.MethodsUtilizing a mouse model to induce ALI, the study analyzed GBP4 expression in alveolar macrophages. By overexpressing or knocking down GBP4, the study assessed its impact on M1 macrophage polarization. The role of YTHDF1 was also explored through knockdown experiments to determine its effect on GBP4 expression and macrophage polarization.ResultsIncreased GBP4 expression was noted in ALI model mice, promoting M1 macrophage polarization. YTHDF1 was found to enhance GBP4 expression by recognizing m6A sites on its mRNA, which was linked to reduced inflammation in MLE-12 cells upon YTHDF1 knockdown.ConclusionThe study emphasizes the crucial roles of GBP4 and YTHDF1 in ALI development and immune response regulation. It suggests m6A modification as a potential therapeutic target, contributing to the understanding of ALI’s molecular mechanisms and guiding future treatment strategies.

Adaptive immune cells antagonize ILC2 homeostasis via SLAMF3 and SLAMF5.

Type 2 innate lymphoid cells (ILC2s) mainly reside in tissues with few lymphoid cells. How their tissue residency is regulated remains poorly understood. This study explores the inhibitory role of SLAM-family receptors (SFRs) on adaptive immune cells in ILC2 maintenance. We observed an increase in the population of ILC2s in Rag1-deficient mice. Homotypic engagement of SFRs between ILC2s and adaptive immune cells was identified as a potential mechanism. SFR deficiency led to an increase in ILC2s. Conditional deletion of SFRs on T and/or B cells led to an increased ILC2 abundance. Mechanistically, as ILC precursors differentiate into ILC2s, SFRs, primarily SLAMF3 and SLAMF5, are inhibitory, which impair IL-7-induced PI3K activation and enhance apoptosis via SHP-1. These findings reveal a mechanism by which adaptive immune cells negatively regulate the homeostasis of ILC2s and contribute to our understanding of the complex interplay between innate and adaptive immune cells in the regulation of immune responses.

Tracheal tuft cells release ATP and link innate to adaptive immunity in pneumonia

Tracheal tuft cells shape immune responses in the airways. While some of these effects have been attributed to differential release of either acetylcholine, leukotriene C4 and/or interleukin-25 depending on the activating stimuli, tuft cell-dependent mechanisms underlying the recruitment and activation of immune cells are incompletely understood. Here we show that Pseudomonas aeruginosa infection activates mouse tuft cells, which release ATP via pannexin 1 channels. Taste signaling through the Trpm5 channel is essential for bacterial tuft cell activation and ATP release. We demonstrate that activated tuft cells recruit dendritic cells to the trachea and lung. ATP released by tuft cells initiates dendritic cell activation, phagocytosis and migration. Tuft cell stimulation also involves an adaptive immune response through recruitment of IL-17A secreting T helper cells. Collectively, the results provide a molecular framework defining tuft cell dependent regulation of both innate and adaptive immune responses in the airways to combat bacterial infection.