Immunology Letters[JOURNAL]
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200 papers
miR-125a-5p regulates Treg function by targeting Foxp3 in experimental autoimmune myasthenia gravis mice.
Tan S, Liu J, Chen L … +2 more , Li R, Li J
Immunol Lett · 2025 Dec · PMID 40490083 · Publisher ↗
MicroRNAs are a class of endogenous noncoding small RNAs. miR-125a-5p is involved in immunoregulatory mechanisms in autoimmune diseases. Myasthenia gravis (MG) is an autoimmune disease in which regulatory T cells (Tregs)...
MicroRNAs are a class of endogenous noncoding small RNAs. miR-125a-5p is involved in immunoregulatory mechanisms in autoimmune diseases. Myasthenia gravis (MG) is an autoimmune disease in which regulatory T cells (Tregs) exhibit reduced numbers and functional defects, with decreased expression of the Treg cell-specific transcription factor Foxp3. Our previous study identified an abnormally high expression of miR-125a-5p in thymoma-associated myasthenia gravis, however, the involvement of miR-125a-5p in the pathogenesis of myasthenia gravis in vivo is unclear. In this study, we explored the role of thymic miR-125a-5p abnormalities in the pathogenesis of myasthenia gravis by establishing an experimental autoimmune myasthenia gravis model. Muscle strength score, low-frequency repetitive nerve stimulation, and serum acetylcholine receptor antibody were performed. The relative expression of miR-125a-5p and Foxp3 in the thymus and spleen was quantified, and the percentage of Treg cells, the levels of the inhibitory cytokines IL-10 and TGF-β1, and the proliferative capacity of splenic T lymphocytes were detected. Our findings revealed significant upregulation of miR-125a-5p expression in myasthenia gravis models. Reducing miR-125a-5p levels alleviated muscle weakness symptoms, elevated Foxp3 expression, enhanced the number of Treg cells, elevated the levels of the Treg-associated inhibitory cytokines IL-10 and TGF-β1, and inhibited the proliferative function of splenic T lymphocytes. The opposite result was obtained when miR-125a-5p was overexpressed. These results suggest that miR-125a-5p can inhibit Foxp3 expression, leading to a decrease in the number and abnormal function of Treg cells. Thus, our findings suggest that miR-125a-5p participates in the pathogenesis of myasthenia gravis by targeting Foxp3 to regulate the function of Treg cells, providing new insights to explore the immunoregulatory mechanisms of miR-125a-5p in myasthenia gravis.
Innate lymphoid cells: Dual roles and therapeutic opportunities in breast cancer.
Mojić M, Radulović N, Bobić S … +3 more , Radenković S, Cruz-Adalia A, Stojanović I
Immunol Lett · 2025 Dec · PMID 40490082 · Publisher ↗
Innate lymphoid cells (ILC) play a crucial role in shaping immune responses and maintaining tissue homeostasis. Recent research has identified their involvement in breast cancer pathogenesis, mainly through shaping the t...
Innate lymphoid cells (ILC) play a crucial role in shaping immune responses and maintaining tissue homeostasis. Recent research has identified their involvement in breast cancer pathogenesis, mainly through shaping the tumor microenvironment, where they can exert dual roles, either promoting tumor eradication by enhancing anti-tumor immunity, or facilitating tumor progression through mechanisms of immune evasion. This functional plasticity makes ILC attractive targets for immunotherapy. Furthermore, their slow proliferation enables them to survive anti-proliferative radiation therapy and chemotherapy, which may support continuous immune surveillance of breast cancer tissue. However, this same resilience poses a significant challenge, as surviving ILC could contribute to tumor persistence or recurrence. Additionally, anti-estrogen therapy, chemotherapy and immune checkpoint inhibitors, commonly used in breast cancer treatment, may interfere with ILC function, either dampening their anti-tumor potential or enhancing their pro-tumor activities. Understanding the complex interactions between ILC and conventional therapies is critical for designing effective immunotherapeutic approaches that include ILC targeting, potentially overcoming resistance and improving patient outcomes in breast cancer therapy.
Human keratinocytes exposed to a clinical strain of Leishmania tropica can result in parasite internalization.
El Idrissi Saik I, Prat-Luri B, Hauyon-La Torre Y … +3 more , Lemrani M, Riyad M, Tacchini-Cottier F
Immunol Lett · 2025 Jun · PMID 40490081 · Publisher ↗
Cutaneous Leishmaniasis (CL) due to Leishmania tropica is a public health burden in Morocco. The increasing clinical polymorphism challenges its proper diagnosis and treatment. Although the immunopathogenesis of CL due t...
Cutaneous Leishmaniasis (CL) due to Leishmania tropica is a public health burden in Morocco. The increasing clinical polymorphism challenges its proper diagnosis and treatment. Although the immunopathogenesis of CL due to L. tropica has been documented, the role of keratinocytes, a critical cell type in skin immunity, has never been investigated in this pathology. Overall, keratinocytes play a crucial role in the recognition and early immune response to Leishmania parasites upon skin inoculation, influencing the local immune response by producing early cytokines that shape anti-leishmanial immune responses. Moreover, they respond differently to each Leishmania species, influencing disease outcomes and helping create a unique microenvironment tailored to each species, thus affecting disease progression. Herein, we have conducted in vitro infection of the human keratinocytes HaCaT cell line with Moroccan clinical strains of L. tropica and L. major. Through flow cytometry and imaging flow cytometry, we show that keratinocytes are infected with both Leishmania species and that they internalize L. tropica parasites. We also report that infection with L. tropica exhibits a higher infection frequency in keratinocytes compared to L. major. These findings support the potential involvement of keratinocytes in the early stages of cutaneous infection. However, further investigations are required to elucidate their role in modulating the local immune response. Our study is a first step in the investigation of keratinocytes involvement during CL due to L. tropica and opens new perspectives for research into CL-specific skin immune mechanisms.
The emerging role of GlycoRNAs in immune regulation and recognition.
Montag N, Gousis P, Wittmann J
Immunol Lett · 2025 Dec · PMID 40451487 · Publisher ↗
Glycosylation, the enzymatic attachment of glycans to biomolecules, is a vital post-translational modification that impacts protein stability, immune recognition, and cellular communication. Traditionally associated with...
Glycosylation, the enzymatic attachment of glycans to biomolecules, is a vital post-translational modification that impacts protein stability, immune recognition, and cellular communication. Traditionally associated with proteins and lipids, recent discoveries have revealed the existence of glycosylated RNAs (glycoRNAs), expanding our understanding of RNA modifications. GlycoRNAs challenge conventional paradigms by suggesting that glycosylation may regulate RNA stability, localization, and interactions with glycan-binding proteins, such as sialic acid-binding immunoglobulin-type lectins (Siglecs) and selectins. These interactions are particularly significant in the immune system, where glycosylation plays a key role in antigen recognition, immune cell trafficking, and pathogen detection. The potential implications of glycoRNAs in immune regulation and disease are profound, with roles in autoimmune disorders, cancer, and infectious diseases. Advances in glycobiology, including mass spectrometry, RNA sequencing, glycan microarrays, and click chemistry technologies, are driving the growth of glycoRNA research and its translational applications. Understanding glycoRNAs could lead to new therapeutic opportunities, including glycoengineering, biomarker discovery, and targeted immune interventions. Despite challenges including low abundance and complex structure, research into glycoRNA is progressing rapidly, revealing their roles in immune responses and disease mechanisms. This review synthesizes the current knowledge on glycoRNAs, highlighting their emerging significance in immunology and outlining future research directions.
DUSP14 attenuates airway inflammation and mucus hypersecretion in allergic asthma by regulating TAK1 activity.
Kong R, Bai J, Yao Q … +1 more , Xu X
Immunol Lett · 2025 Dec · PMID 40449853 · Publisher ↗
Allergic asthma is characterized by persistent chronic airway inflammation, leading to mucus hypersecretion and airway hyperresponsiveness. Dual-specificity phosphatase 14 (DUSP14), a member of the DUSP family, is a key...
Allergic asthma is characterized by persistent chronic airway inflammation, leading to mucus hypersecretion and airway hyperresponsiveness. Dual-specificity phosphatase 14 (DUSP14), a member of the DUSP family, is a key regulator in various biological processes. However, the function of DUSP14 in allergic asthma remains to be elucidated. In this study, we aim to explore the function and mechanism of DUSP14 in asthma-related airway inflammation. In an ovalbumin (OVA) asthma mouse model, DUSP14 was found to be significantly diminished. DUSP14 overexpression relieved airway inflammation and attenuated airway mucus production. In vitro, overexpression of DUSP14 attenuated IL-13-induced cellular inflammation and mucus hypersecretion in bronchial epithelial cells (BEAS-2B). Afterwards, we used the co-immunoprecipitation assay to confirm that DUSP14 interacted with TAK1. DUSP14 overexpression restrained the activation of TAK1 and NF-κB signaling pathway in vitro and in vivo. Taken together, our findings clearly showed that DUSP14 could alleviate airway inflammation by inhibiting TAK1 activity and NF-κB signaling pathway, positioning the DUSP14-TAK1-NF-κB regulatory axis as a potential therapeutic target for allergic asthma.
Electrostatic potential is the dominant force in antigenic selection of naïve T-cells and B-cells for activation and maturation.
Nand KN, Bystroff C
Immunol Lett · 2025 Dec · PMID 40414461 · Publisher ↗
Peptide antigenicity can be predicted from sequence using a simple method invented by Hopp and Woods in the early 1980's. Since then, a much clearer understanding of T-cell/B-cell signaling and maturation calls for a new...
Peptide antigenicity can be predicted from sequence using a simple method invented by Hopp and Woods in the early 1980's. Since then, a much clearer understanding of T-cell/B-cell signaling and maturation calls for a new understanding of the amino acid determinants of antigenicity. We show that short peptides with more charged side chains generate significantly higher titers of peptide specific antibodies in co-immunized mice. Peptide docking simulations using linearized Poisson-Boltzmann calculations of electrostatic potential show that immunoglobulins distinguish the cognate peptide sequence from randomly selected sequences at "arms length" (10-20 Å) with >70 % of alternative sequences having higher energy at this distance, consistent with the weak specificity observed for naive T-cell and B-cell receptor interactions with MHC-bound antigen. Orders of magnitude lower complexity of the state space of charged surfaces as compared to the state space of surface shapes suggests a dominant role of electrostatics in selecting naive immune cells from the population of circulating cell lines. We propose a two-stage antigen recognition process, first electrostatic and then shape-based, that explains the dominant contribution of charged residues to peptide immunogenicity.
Increased expression of membrane-bound TGF-β1, GITR, and GITR ligand in patients with autoimmune thyroid disease.
Hayashi F, Inoue N, Iwatani Y … +4 more , Yamashita Y, Yamada H, Miyauchi A, Watanabe M
Immunol Lett · 2025 Dec · PMID 40412445 · Publisher ↗
Regulatory T (Treg) cells, which play an important role in maintaining self-tolerance, are present in the thyroid-infiltrating lymphocytes of patients with autoimmune thyroid disease (AITD). We examined the expression of...
Regulatory T (Treg) cells, which play an important role in maintaining self-tolerance, are present in the thyroid-infiltrating lymphocytes of patients with autoimmune thyroid disease (AITD). We examined the expression of membrane-bound transforming growth factor-β1 (mTGF-β1), which mediates regulatory function and glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR). The protein in turn may inhibit regulatory function on Treg cells and TGF-β1 receptor II (TGF-βRII) and GITR expression. We also evaluated GITR ligand (GITRL) localization in thyroid tissues. mTGF-β1 cells proportion in Treg cells was higher in the thyroid of patients with AITD than in their peripheral blood. GITR cells proportion among Tregs and Teff cells was also higher in the thyroid than in peripheral blood. GITRL expression in thyrocytes was higher in AITD patients than in healthy subjects. The interaction and balance of mTGF-β1, GITR, TGF-βRII, and GITRL especially thyrocyte GITRL expression, could be critical in AITD pathogenesis.
The role of DAMP cytotoxic fractions in the immune markers' disruption in patients with urgent surgical pathology and against the background of post-COVID-19 syndrome.
Klimova EM, Lavinska OV, Drozdova LA
Immunol Lett · 2025 Dec · PMID 40409597 · Publisher ↗
BACKGROUND: As a result of the SARS-CoV-2 pandemic, various population groups were formed that had acute and asymptomatic COVID-19. A survey in these groups revealed with equal frequency an asthenic symptom complex, the...
BACKGROUND: As a result of the SARS-CoV-2 pandemic, various population groups were formed that had acute and asymptomatic COVID-19. A survey in these groups revealed with equal frequency an asthenic symptom complex, the so-called post-COVID-19 syndrome (PCS). The frequency of urgent surgical pathology against the background of PCS and structural and functional disorders of various organs was increased. The aim - to study the dynamics of immunoresistance factors changes in patients with urgent surgical pathology that developed against the background of PCS and to identify pathogenic markers of the severe course and the risk of mortality. MATERIALS AND METHODS: To examine patients with PCS and urgent cardiovascular (n = 103) and abdominal (n = 106) pathology we used the following methods: fluorescence microscopy, confocal microscopy, flow cytometry, spectrophotometry, ELISA. RESULTS: We revealed a temporal dependence of immune dysfunction in patients with a comorbid course of urgent surgical pathology and PCS. The nature of the DAMP (damage-associated molecular patterns) cytotoxic fractions ratio was associated with certain changes in innate and adaptive immunity factors, severity of the condition and risk of mortality. At the first stage (2020-2021), patients with PCS has disorders of the humoral and cellular components of innate immunity against the background of an increase in the oligopeptide and peptide DAMP fractions. At the second stage (2022-2024) of PCS development, changes in innate as well as adaptive immunity were observed against the background of an increase in the cytotoxic oligonucleotide DAMP fraction (mortality was 17.3 %). CONCLUSIONS: The identified markers of impaired immunoresistance in cardiovascular and abdominal urgent pathology can be used to select targeted therapy tactics.
Dynactin subunit 1 facilitates mast cell degranulation to drive food allergy pathogenesis.
Zhao M, Zhang H, Liu Z … +9 more , Liu J, Xie B, Zeng L, Wang X, Shu Q, Tang P, Mo L, Zeng H, Yang P
Immunol Lett · 2025 Dec · PMID 40404107 · Publisher ↗
BACKGROUND: Mast cells play pivotal roles in allergic pathogenesis and inflammatory disorders, with their pathologic effects largely mediated through granule exocytosis. Dynactin subunit 1 (Dctn1), a microtubule-associat...
BACKGROUND: Mast cells play pivotal roles in allergic pathogenesis and inflammatory disorders, with their pathologic effects largely mediated through granule exocytosis. Dynactin subunit 1 (Dctn1), a microtubule-associated motor protein, remains unexplored in mast cell-driven inflammation. This study investigates Dctn1's functional role in regulating mast cell degranulation during food allergy (FA). METHODS: An ovalbumin-sensitized murine FA model was established to profile mast cell activity. Gut lavage fluid (GLF) was analyzed via Olink proteomics and ELISA to quantify Dctn1 levels and mast cell mediators (histamine, Mcpt1). Mechanistic studies employed RNA interference, conditional knockout mice (Dctn1Cma1-Cre), and immunoprecipitation to assess Dctn1's role in granule trafficking. RESULTS: FA mice exhibited 3.2-fold higher Dctn1 levels in GLF versus controls (p < 0.001), strongly correlating with mast cell mediator concentrations (histamine: r = 0.73; Mcpt1: r = 0.7). Intestinal mast cells showed selective Dctn1 upregulation (2.8-fold mRNA increase, p < 0.01), mechanistically linked to granule trafficking through CMA1 complex formation. Mast cell-specific Dctn1 ablation reduced Mcpt1 release by 74 % (p < 0.001) and ameliorated FA symptoms (92 % core temperature drop, p < 0.005), independent of AKT/ERK signaling pathways. CONCLUSIONS: This study identifies Dctn1 as a novel regulator of mast cell degranulation in FA, operating through microtubule-dependent granule transport. Targeted inhibition of Dctn1 significantly attenuates allergic responses without disrupting canonical activation signals, positioning it as a promising therapeutic target for mast cell-driven pathologies.
Attenuated notch signaling decreases T-cell factor-1+ Treg subsets in lung adenocarcinoma, assisting early patient screening.
Bahabayi A, Zheng M, Hasimu A … +8 more , Kang R, Li Q, Xiong Z, Guan Z, Zhang Z, Liu T, Zeng X, Liu C
Immunol Lett · 2025 Dec · PMID 40404106 · Publisher ↗
OBJECTIVE: This study aimed to investigate the role of T-cell factor-1 (TCF1) in early-stage lung adenocarcinoma (LUAD) patients and explore its clinical significance for diagnosing early LUAD. METHODS: Blood samples wer...
OBJECTIVE: This study aimed to investigate the role of T-cell factor-1 (TCF1) in early-stage lung adenocarcinoma (LUAD) patients and explore its clinical significance for diagnosing early LUAD. METHODS: Blood samples were collected from 34 stage IA LUAD patients and 31 healthy controls. Flow cytometry was used to analyze the levels of TCF1 in circulating T cell subpopulations. Functional characteristics of TCF1-related cells were investigated by staining with CD62L and Ki-67. Changes in TCF1-related proportions in T cell subsets of early LUAD patients were analyzed. The role of Notch signaling was clarified by adding the Notch signal activator Jagged1 (JAG1). Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic value of TCF1-related T cell subsets for screening early LUAD. RESULTS: The expression level of TCF1 in follicular regulatory T(Tfr) and regulatory T(Treg) cells was decreased in early LUAD patients, and TCF1+CD62L+ follicular helper (Tfh) cells were also decreased. TCF1+CD62L+ cells in both Treg and Tfr were decreased in early LUAD patients. Decreased TCF1 in Treg and Tfr recovered in early LUAD after adding JAG1. TCF1-related indicators showed good auxiliary diagnostic significance for early LUAD. TCF1+, TCF1+CD62L+, and TCF1-CD62L+ percentages in Treg and Tfr cells were with areas under the curve (AUCs) between 0.827 and 0.897 to distinguish early LUAD from healthy individuals. CONCLUSIONS: Downregulation of Notch signaling contributes to the decrease in TCF1+ Treg subsets in LUAD patients, which is of significant value for screening early-stage lung adenocarcinoma.
Inhibition of FOSL1 alleviates inflammatory injury of otitis media by reducing ferroptosis.
Liu Z, Zhang F, Jia F … +2 more , Yu Y, Long R
Immunol Lett · 2025 Dec · PMID 40379053 · Publisher ↗
OBJECTIVES: Otitis media (OM) is a disease involving inflammation and infection of the middle ear that primarily affects children. Fos-like antigen 1 (FOSL1), a component of AP1 transcription factor complexes, is a key r...
OBJECTIVES: Otitis media (OM) is a disease involving inflammation and infection of the middle ear that primarily affects children. Fos-like antigen 1 (FOSL1), a component of AP1 transcription factor complexes, is a key regulator in inflammation and various diseases. However, the role of FOSL1 in OM remains largely unknown. Our study aimed to elucidate the function and mechanism of FOSL1 in OM. METHODS: The gene expression dataset was obtained from Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) from OM mice and control mice were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyzes were used to identify potential biological pathways. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were performed to excavate the biological signaling pathways. The OM cell model was induced by Staphylococcus aureus and Bacillus cereus administration. The expression of FOSL1 and ferroptosis-related proteins in OM cell model were determined by western blot. Inflammatory cytokines in cells were detected by qPCR. RESULTS: DEGs was identified from gene set enrichment (GSE) 49128, 441 genes were up-regulated and 180 were down-regulated. FOSL1 was highly expressed in OM mice. Consistent with the bioinformatic analysis, the expression of FOSL1 in bacterial-induced OM cells was upregulated. Inhibition of FOSL1 via siRNA alleviated the inflammatory response and cell ferroptosis in the OM cell model. The reduced level of inflammatory cytokines and cell ferroptosis induced by FOSL1 inhibition could be rescued by ferroptosis activator erastin. CONCLUSION: FOSL1 inhibition could alleviate release of inflammatory cytokines and ferroptosis in the OM cell model.
Low IL-35 expression in CSF is associated with Neuro-Behcet Disease: Comparative analysis between parenchymal and Non-parenchymal NBD.
Hamzaoui K, Sassi F, Salhi M … +1 more , Hamzaoui A
Immunol Lett · 2025 Oct · PMID 40360083 · Publisher ↗
BACKGROUND: IL-35 is a recently discovered immunoregulatory cytokine that inhibits inflammatory cytokines by suppressing their lineage-specific transcription factors. The objective of this study was to investigate the ex...
BACKGROUND: IL-35 is a recently discovered immunoregulatory cytokine that inhibits inflammatory cytokines by suppressing their lineage-specific transcription factors. The objective of this study was to investigate the expression of IL-35 in the cerebrospinal fluid (CSF) of patients with Neuro-Behçet Disease (NBD). An immuno-comparative analysis was performed between parenchymal NBD (pNBD) and non-parenchymal NBD (npNBD). METHODS: We are investigating CSF IL-35 levels in 45 patients with (NBD), comprising 25 patients with pNBD and 20 with npNBD, compared to 27 patients with multiple sclerosis (MS) and 20 patients with non-inflammatory neurological diseases (NIND). We assessed the inflammatory cytokines (IL-1α, IL-18, IL-33, IL-36), Foxp3 and CD4 CD25 Foxp3 regulatory Treg T cells (Tregs). The following methodologies were employed: flow cytometry, ELISA, and real-time polymerase chain reaction (RT-PCR). For RT-PCR analysis, we calculated relative gene expression in target genes using the comparative CT method with the equation 2. We employed a receiver operating characteristic (ROC) curve to investigate the predictive value of IL-35 levels. RESULTS: Protein and relative mRNA expression of IL-35 were significantly decreased in NBD and MS patients compared to the NIND group. Significantly lower CSF IL-35 mRNA (p= 0.0001) and protein (p= 0.0004) were observed in patients with pNBD compared to npNBD. The study revealed that NBD patients exhibited low Treg counts, and a significant positive correlation was identified between Treg numbers and CSF IL-35 (r = 0.554, p= 0.0001). Negative associations were observed between Tregs and CRP (r =- 0.518; p= 0.0001) and ESR (r = -0.571; p= 0.0001) in NBD. Levels of the pro-inflammatory mediators were found to be elevated in contrast to a low Foxp3 level in NBD, which was more reduced in pNBD compared to npNBD. In vitro cultured memory T cells from pNBD patients stimulated with LPS showed high levels of IL-1α, IL-18, IL-33, IL-36 and low levels of Foxp3 and IL-35 measured in the culture medium. After the addition of recombinant human IL-35 (rhIL-35), Foxp3 and IL-35 were significantly increased and inflammatory cytokine levels were reduced. These results suggest that rhIL-35 may induce a regulatory effect on Foxp3 and IL-35. CONCLUSION: These findings imply a critical reduction of IL-35 in pNBD patients. The combined protein and gene expression of the tested inflammatory cytokines suggest that there are distinct inflammatory mechanisms governing the central nervous system in pNBD. Further work is essential for the development of targeted interventions for the effective treatment of patients.
Quercetin improves macrophage immune regulatory functions to alleviate airway Th2 polarization.
Dong Y, Liu L, Zhang X … +7 more , Zheng H, Liu Y, Zhang A, Xu L, Zhang Y, Yang G, Yang P
Immunol Lett · 2025 Oct · PMID 40316181 · Publisher ↗
BACKGROUND: Th2 polarization is a central driver of allergic airway inflammation, yet the epigenetic mechanisms underlying its dysregulation remain poorly defined. Quercetin is a bioactive flavonoid with immunomodulatory...
BACKGROUND: Th2 polarization is a central driver of allergic airway inflammation, yet the epigenetic mechanisms underlying its dysregulation remain poorly defined. Quercetin is a bioactive flavonoid with immunomodulatory properties. This study investigates whether quercetin alleviates Th2-driven pathology in allergic airway inflammation by targeting IL-10 promoter hypermethylation in airway M2 macrophages. METHODS: Using a murine model of house dust mite (Derf2)-induced allergic airway inflammation, we isolated airway M2 macrophages via flow cytometry and assessed their immunosuppressive capacity using CFSE-based T cell proliferation assays. Epigenetic regulation of Il10 was analyzed by bisulfite sequencing and chromatin immunoprecipitation. Quercetin (intranasal) was administered daily for 7 days. RESULTS: Allergic mice exhibited impaired M2 cell-mediated T cell suppression (proliferation index: 85% vs. 34% in controls, P < 0.01) and IL-10 deficiency in bronchoalveolar lavage fluid (8.5 pg/ml vs. 28.2 pg/ml, P <0.001). Il10 promoter hypermethylation (72% vs. 35% methylation at CpG sites -200 to +100) and reduced KDM5A recruitment were observed in M2 cells from allergic mice. Quercetin treatment reversed these epigenetic defects, restoring KDM5A binding (P < 0.05) and Il10 transcription (2.1-fold increase, P < 0.01), thereby reducing Th2 cytokines and airway hyperresponsiveness. CONCLUSIONS: Our findings identify KDM5A-mediated Il10 promoter demethylation as a critical mechanism for M2 cell immunoregulation in allergic airway inflammation. Quercetin alleviates Th2-driven pathology by restoring Il10 expression via epigenetic reprogramming of M2 macrophages. This study advances the understanding of natural compounds in targeting epigenetic checkpoints and provides a rationale for quercetin-based therapies in allergic diseases.
Platelet-derived microvesicles modulate cytokine and lipid mediator profiles in THP-1 monocytes and macrophages.
Foulem RD, Mbarik M, Doiron JA … +6 more , Soucy MN, Toro-Ramirez D, Pecourt F, Barnett DA, Boudreau LH, Surette ME
Immunol Lett · 2025 Oct · PMID 40306329 · Publisher ↗
Monocytes are circulating immune cells that migrate to inflamed tissues and differentiate into macrophages, where they play a dual role in regulating pro-inflammatory and pro-resolving responses through cytokine and lipi...
Monocytes are circulating immune cells that migrate to inflamed tissues and differentiate into macrophages, where they play a dual role in regulating pro-inflammatory and pro-resolving responses through cytokine and lipid mediator secretion. Platelet-derived microvesicles (PMVs), released during platelet activation, infiltrate inflamed areas and interact with monocytes and macrophages, facilitating the transfer of bioactive contents. While these interactions have been observed, their functional consequences on monocyte/macrophage inflammatory profiles remain poorly understood. In this study, PMVs are shown to be internalized by human THP-1 monocytes. The interaction with THP-1 cells occurs rapidly, with 60 % of cells interacting with PMVs within one hour. When cells are differentiated to M and M macrophages, interactions with PMVs only peak after 24 h. Interaction of cells with PMVs resulted in an increased capacity to synthesize cyclooxygenase- and lipoxygenase-derived lipid mediators of inflammation, especially in M cells. Cytokine production was also influenced in a cell-state-dependent manner. PMVs had no impact on undifferentiated THP-1 cells but enhanced the production of several cytokines in M cells as well as IL-23 and IL-6 in M macrophages. When stimulated with lipopolysaccharides, PMV-treated M macrophages demonstrated elevated production of the anti-inflammatory cytokine IL-10, while M1 macrophages exhibited increased secretion of IL-1β, MCP-1, and IL-6, highlighting an effect on pro-inflammatory cytokine production. These findings reveal that PMVs selectively modulate the inflammatory cytokine and lipid mediator profiles of monocytes and macrophages depending on their differentiation state. This study underscores the role of PMVs as key players in intercellular communication and immune regulation, particularly in the context of inflammation.
Unveiling the hidden syndrome: The enigma of anti-transcobalamin receptor autoantibodies.
Matsuda KM, Kotani H, Sato S … +1 more , Yoshizaki A
Immunol Lett · 2025 Oct · PMID 40280282 · Publisher ↗
The transcobalamin receptor (CD320) functions as a critical mediator for vitamin B12 uptake in cells, with emerging evidence linking autoantibodies against CD320 to various autoimmune conditions. Pluvinage et al.'s recen...
The transcobalamin receptor (CD320) functions as a critical mediator for vitamin B12 uptake in cells, with emerging evidence linking autoantibodies against CD320 to various autoimmune conditions. Pluvinage et al.'s recent study identified anti-CD320 autoantibodies as a cause of autoimmune vitamin B12 central deficiency, specifically affecting the central nervous system while sparing peripheral nerves. Their findings align with our previous work showing anti-CD320's role in cutaneous arteritis. Both studies identified overlapping CD320 epitopes targeted by autoantibodies and demonstrated the therapeutic efficacy of high-dose vitamin B12 supplementation in mitigating symptoms. Expanding on these findings, we observed anti-CD320 autoantibodies in other inflammatory disorders such as systemic sclerosis, suggesting a broader clinical relevance. The work by Pluvinage et al. and our group supports the concept of an "anti-CD320-associated syndrome," with high-dose B12 supplementation as a promising treatment strategy. Further research is needed to fully elucidate the tissue-specific mechanisms and pathophysiology underlying these autoimmune conditions.
Identification of S100A9 as a target for diagnosis and treatment of Crohn's Disease after Vedolizumab treatment failure.
Zhang Y, Zhang Z, Liu R … +12 more , He Y, Ning S, Yu J, Liu Y, Xia Y, Pang X, Lv W, Sun Q, Li Y, Wang Z, Liu L, Feng B
Immunol Lett · 2025 Oct · PMID 40280281 · Publisher ↗
The vedolizumab medication is the treatment that precisely targets the gut for Crohn's Disease (CD). It can inhibit the migration of lymphocytes to the intestinal site despite the fact that a significant portion of the p...
The vedolizumab medication is the treatment that precisely targets the gut for Crohn's Disease (CD). It can inhibit the migration of lymphocytes to the intestinal site despite the fact that a significant portion of the population continues to be ineffectively treated. In this study, peripheral blood leukocytes sampled from the CD patients who are nonresponsive or responsive to vedolizumab treatment were used for transcriptome sequencing. Intersected differentially expressed mRNA obtained from transcriptome sequencing and GSE191328 were utilized to predict key therapeutic targets. Bioinformatics analyses were used to explore potential biological mechanisms and to screen pivotal genes. Inhibitor of S100A9 increased the body weight and colon length of mice with colitis, and decreased the DAI score. Our study also demonstrated that the combination of anti-α4β7 integrin antibody with inhibitor of S100A9 further alleviates colitis. Through flow cytometry, changes in the composition of immune cell populations in colon tissues were found after intragastric administration of paquinimod, an inhibitor of S100A9. It is important that blocking S100A9 inhibited the recruitment of neutrophils in the mice's colon. Our findings lay a foundation for the further exploration of the new targets for non-responders to vedolizumab in CD patients.
NETs activate AIM2 to mediate synovial fibroblast pyroptosis and promote acute gouty arthritis development.
Tian J, Liu Y, Gao W … +3 more , Shi X, Cheng F, Xie B
Immunol Lett · 2025 Oct · PMID 40267802 · Publisher ↗
BACKGROUND: Acute gouty arthritis is a metabolic disease characterized by hyperuricemia, with acute attacks involving neutrophil-released NETs activating immune responses through their major component, DNA, as danger-ass...
BACKGROUND: Acute gouty arthritis is a metabolic disease characterized by hyperuricemia, with acute attacks involving neutrophil-released NETs activating immune responses through their major component, DNA, as danger-associated molecular patterns (DAMPs). OBJECTIVE: To investigate whether DNA from NETs activates the AIM2 inflammasome in synovial fibroblasts during acute gouty arthritis attacks, inducing pyroptosis and exacerbating inflammation. METHODS: The AIM2 gene knockdown mouse model of acute gouty arthritis was constructed, the joint pathological changes were observed by H&E staining, the synovium fibroblasts and neutrophils were sorted by flow cytometry, and the expressions of AIM2, Caspase-1 and GSDMD related proteins were detected by Western blot. The levels of TNF-α, IL-6, IL-1β and IL-18 in serum and cell supernatant were detected by ELISA. Neutrophils were induced to release NETs by urate, and NETs markers (dsDNA, MPO-DNA, NE-DNA) were detected by immunofluorescence (Cit-H3, PAD4) and ELISA. NETs media were co-cultured with synovial fibroblasts, cell activity and migration were evaluated by CCK8 and scrape assay, markers of synovitis (Thy1, VCAM-1, PDPN) were detected by immunofluorescence, and pyroptosis was evaluated by TUNEL and LDH release. By silencing or overexpression of AIM2 gene, Western blot and ELISA, the role of AIM2 in NETs induced pyrodeath and inflammatory response was investigated. RESULTS: AIM2 gene knockdown significantly alleviated the symptoms of MSU-induced acute gouty arthritis in mice, reducing joint swelling and pathological damage. Expression levels of inflammatory factors (TNF-α, IL-6, IL-1β, IL-18) and cleaved Caspase-1/Caspase-1, GSDMD-NT/GSDMD) were decreased. It was found that neutrophils released NETs in response to sodium urate stimulation, manifested by significant upregulation of Cit-H3 and PAD4, as well as increased dsDNA, MPO-DNA, and NE-DNA complexes. NETs can induce inflammatory response in synovial fibroblasts, which is manifested as decreased cell activity and migration ability, increased release of inflammatory factors, and significantly increased markers of synovitis (Thy1, VCAM-1, PDPN). In addition, NETs induce scorch death of synovium fibroblasts by activating AIM2 inflammatories, which aggravates the inflammatory response, and AIM2 gene knockdown can effectively inhibit the scorch death and inflammatory response induced by NETs, indicating that NETs play a key role in the occurrence and development of gout arthritis through AIM2-mediated scorch death of synovium fibroblasts. CONCLUSION: NETs-activated AIM2-mediated synovial fibroblast pyroptosis plays a crucial role in acute gouty arthritis, providing a new therapeutic target.
Mast cell activation signature as a potential biomarker in COVID-19.
Meneses-Preza YG, Soria-Castro R, Alfaro-Doblado ÁR … +14 more , Hernández-Solis A, Álvarez-Maldonado P, Gómez-Martín D, Torres-Ruiz J, Muñoz-Valle JF, Muñoz-Ríos G, Hernández-Ramírez CO, Güemes-González AM, Wong-Baeza I, Maravillas-Montero JL, Pérez-Tapia SM, Chávez-Blanco AD, Estrada-Parra S, Chacón-Salinas R
Immunol Lett · 2025 Oct · PMID 40250770 · Publisher ↗
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, represented a public health challenge due to the absence of effective treatments to combat the disease. Lethality associated with SARS-CoV-2 infection results from a...
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, represented a public health challenge due to the absence of effective treatments to combat the disease. Lethality associated with SARS-CoV-2 infection results from an exacerbated immune response that mediates clinical disease progression and compromises respiratory capacity and organ function. In the lungs, one of the cell lineages increased during COVID-19 are mast cells (MC), cells of innate immune response known for their ability to promote inflammation through the release of their pre-formed mediators or de novo synthesis. The role of MC-derived mediators during SARS-CoV-2 infection and their association with the development of severe COVID-19 have been poorly described. In a previous report, we demonstrated the predictive ability of carboxypeptidase A3 (CPA3) to determine COVID-19 severity. However, it is currently unclear whether the use of other mast cell-derived mediators could improve this predictive ability. To address this gap, we evaluated levels of total tryptase, CPA3, chymase, and prostaglandin D2 (PGD2) in serum from patients with non-severe and severe COVID-19 to develop a predictive model of severe COVID-19 outcomes. We demonstrate that the combined use of these mediators enhances their predictive ability for MC activation during SARS-CoV-2 infection and their involvement in severe forms of COVID-19. Based on these findings, a serum MC activation profile can be proposed as a promising biomarker for SARS-CoV-2 infection and may contribute to the development of targeted therapeutic strategies to improve patient outcomes.
A novel MF59 and CpG1018 adjuvant combination enhances the humoral and cellular immune responses against a truncated varicella-zoster viral glycoprotein E.
Yang J, Hu X, Chen X … +6 more , Li W, Yin Q, Xiong Y, An Y, Li H, Liu Z
Immunol Lett · 2025 Oct · PMID 40239819 · Publisher ↗
Vaccination is the only effective strategy for preventing herpes zoster (HZ), a disease caused by reactivation of the varicella-zoster virus (VZV). Cell-mediated immunity (CMI) plays a pivotal role in controlling VZV rea...
Vaccination is the only effective strategy for preventing herpes zoster (HZ), a disease caused by reactivation of the varicella-zoster virus (VZV). Cell-mediated immunity (CMI) plays a pivotal role in controlling VZV reactivation and is a critical factor in the efficacy of the HZ vaccine. This research introduced the preliminary utilization of truncated glycoprotein E (tgE) as the antigen in the formulation of an innovative recombinant HZ vaccine and explored the combination of tgE with several adjuvants to assess their effectiveness in eliciting robust humoral and CMI responses in C57BL/6 mice, followed by the immunogenicity validation of the optimal vaccine formulation in Sprague-Dawley (SD) rats and cynomolgus monkeys. The results demonstrated that the combination of tgE with MF59 and CpG1018, designated as tgE/MF59+CpG1018, elicited significantly stronger gE-specific humoral and cellular immune responses in C57BL/6 mice compared to any single adjuvant or other adjuvant combinations. The optimal dosages for MF59 and CpG1018 were determined to be 0.025 ml and 10 μg, respectively, for each 0.05 ml of the vaccine formulation. Notably, the increasing in the dosage of the adjuvant does not inherently correlate with a more pronounced immune response. Furthermore, the tgE/MF59+CpG1018 also elicited robust humoral and CMI responses in both SD rats and cynomolgus monkeys. These findings established the novel tgE/MF59+CpG1018 vaccine as a highly promising prophylactic candidate against HZ.
CD4 T-cell help delivery to monocyte-derived dendritic cells promotes effector differentiation of helper and cytotoxic T cells.
Bosma DMT, Busselaar J, Staal MD … +4 more , Frijlink E, Mack M, Salerno F, Borst J
Immunol Lett · 2025 Oct · PMID 40239818 · Publisher ↗
Delivery of CD4 T-cell help optimizes CD8 T-cell effector and memory responses via CD40-mediated licensing of conventional dendritic cells (DCs). Using comparative vaccination settings that prime CD8 T cells in presence...
Delivery of CD4 T-cell help optimizes CD8 T-cell effector and memory responses via CD40-mediated licensing of conventional dendritic cells (DCs). Using comparative vaccination settings that prime CD8 T cells in presence or absence of CD4 T-cell help, we observed that CD4 T-cell activation promoted influx of monocytes into the vaccine-draining lymph nodes (dLNs), where they differentiated into monocyte-derived (Mo)DCs, as defined by the most recent standards. Abrogation of these responses by CCR2-targeted depletion indicated that monocyte-derived cells in the dLN promoted T-helper 1 (Th1) type effector differentiation of CD4 T cells, as well as effector differentiation of CD8 T cells. Monocyte-derived cells in dLNs upregulated CD40, CD80 and PD-L1 as a result of CD4 T-cell help. The response of monocyte-derived cells to CD4 T-cell help was independent of natural killer (NK) cells and proceeded via CD40 ligand (L)-CD40 interactions and IFNγ signaling. Our data argue for a scenario wherein activated CD4 T cells in dLNs crosstalk via CD40L and IFNγ signals to monocytes, promoting their local differentiation into MoDCs. This event enhances formation of CD4 Th1 and CD8 cytotoxic effector T cell pool, most likely by virtue of their improved costimulatory status and cytokine production.
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