Munkh-Erdene T, Saitoh T, Kitamura M
… +13 more, Kojima A, Okawa T, Oda T, Miyauchi E, Sasaki N, Matsumura I, Matsumoto A, Takei H, Kobayashi N, Miyazawa Y, Ogawa Y, Handa H, Gotoh N
BMC Immunol
· 2026 May · PMID 42070020
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BACKGROUND: Inflammatory cytokines influence the pathogenesis and progression of acute myeloid leukaemia (AML), not only by shaping the leukemic microenvironment, but also by supporting leukaemia stem cell survival and r...BACKGROUND: Inflammatory cytokines influence the pathogenesis and progression of acute myeloid leukaemia (AML), not only by shaping the leukemic microenvironment, but also by supporting leukaemia stem cell survival and resistance to therapy. We, therefore, investigated the associations between the cytokine polymorphisms IFNG+874 A/T, TNFA-857 C/T, and IL1B -31 C/T and AML outcomes, as well as their influence on clinical features. RESULTS: Ninety-three patients with AML and 117 healthy controls were analysed. The T allele of TNFA - 857 C/T (i.e., the high-expression allele) was observed at a significantly higher frequency in the patients with AML vs. the controls (AML vs. control = 24.7% vs. 16.2%, p = 0.04). Patients with the high-expression TT genotype had shorter overall survival (TT vs. CC = 46.0 vs. 224.1 months, p < 0.001). Patients with the high-expression non-CC genotype relapsed more frequently than those with the low-expression CC genotype (relapse vs. non-relapse = 55.8% vs. 26.9%, p = 0.01). No significant associations were observed for the IFNG + 874 A/T and IL1B -31 C/T polymorphism. CONCLUSION: TNFA - 857 C/T polymorphisms can influence patient susceptibility to AML, as well as its prognosis. This suggests a link between chronic inflammation and leukemogenesis, as well as the potential value of TNFA genotyping in risk assessments.
Allergic airway inflammation (AA) is primarily driven by the activation of mast cells and eosinophils, with granular exocytosis serving as a key source of pro-allergic mediators that amplify pathological responses. This...Allergic airway inflammation (AA) is primarily driven by the activation of mast cells and eosinophils, with granular exocytosis serving as a key source of pro-allergic mediators that amplify pathological responses. This unmet need highlights the importance of identifying novel, pathway-specific therapeutic targets to improve disease management. A dust mite extract (DME)-induced murine model of AA was used to assess intranasal A13 (1 mg/kg daily) efficacy; human EoL-1 eosinophils and murine P815 mast cells were stimulated with PMA/ionomycin (P&I) to induce exocytosis. In DME-induced murine AA, intranasal A13 reduced lung inflammation by 58% (p < 0.01), serum sIgE by 73% (p < 0.001), and BALF Th2 cytokines (IL-4/IL-5/IL-13) by 65%-80% (p < 0.001), while restoring BALF IFN-γ (p < 0.01). A13 inhibited granular mediator release: in P&I-challenged WT mice, it reduced BALF eosinophil peroxidase (EPX) by 81% and mast cell protease-1 by 85%, but had no effect in APLNR⁻⁻ mice (p > 0.05). Mechanistically, P&I induced Rab27a upregulation (P815: 3.2-fold; EoL-1: 2.8-fold), which A13 reversed in vitro; in vivo, A13 lowered lung granulocyte Rab27a by 2.5-3.1-fold (p < 0.001). A13 engaged APLNR to recruit FBXO28, promoting K48-linked Rab27a ubiquitination and proteasomal degradation. APLNR knockdown or MG132 treatment abrogated A13's effects, while A13 enhanced FBXO28-Rab27a complex formation by 4.7-fold (p < 0.001)-an interaction undetectable in APLNR cells. Intranasal A13 exhibits localised action, effectively suppressing allergic inflammation without broad systemic immunosuppression, making it a promising candidate for development as a topical biologic to treat allergic airway diseases.
Shen Y, Zhang J, Fang H
… +5 more, Zhang L, Jiang Q, Gong H, Chen Q, Zhao M
BMC Immunol
· 2026 Apr · PMID 42062913
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Cesarean scar pregnancy (CSP), a condition characterised by inflammation, occurs in 0.2% of women with a history of cesarean section(s), and is clinically categorised by type 1 and type 2 according to the ultrasound find...Cesarean scar pregnancy (CSP), a condition characterised by inflammation, occurs in 0.2% of women with a history of cesarean section(s), and is clinically categorised by type 1 and type 2 according to the ultrasound findings. Recent studies reported that systemic inflammation indices derived from routine whole-blood tests may serve as additional clinical predictive markers for early CSP detection, with lymphocyte counts showing a reduction. However, the specific lymphocyte populations contributing to this reduction remain unclear. This study included 72 women diagnosed with CSP and 50 gestation-matched controls. The subsets of peripheral lymphocytes, including CD45 lymphocytes/monocytes, CD3 T cells, CD4 T helper cells, CD8 cytotoxic T cells, CD19 B cells, total NK cells and NKT-like cells, were measured. We found a significant reduction in peripheral total NK cells and CD8 cytotoxic T cells in CSP women compared to controls. However, there were no differences in peripheral immune cell profiles between type 1 and type 2 CSP. Using total NK cell counts with a cut-off value of 210/µl, the area under the curve (AUC) was 0.698, with a sensitivity of 64%. Our findings suggest that the reduction in peripheral total NK cells and CD8 T cytotoxic cells may play a role in the development of CSP. Additionally, peripheral total NK cell counts, derived from routine whole-blood tests, could serve as a predictive marker for early CSP diagnosis.
Liu H, Wu L, Chen C
… +3 more, Liu J, Li F, Chen L
BMC Immunol
· 2026 May · PMID 42062862
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BACKGROUND: Pituitary neuroendocrine tumors (PitNETs) derived from adenohypophyseal cells are the third most frequent primary intracranial tumor. PitNETs that invades surrounding anatomical structures such as the caverno...BACKGROUND: Pituitary neuroendocrine tumors (PitNETs) derived from adenohypophyseal cells are the third most frequent primary intracranial tumor. PitNETs that invades surrounding anatomical structures such as the cavernous sinus are defined as invasive PitNETs. Patients with invasive PitNETs often have co-morbidities and high recurrence rates. This study aimed to identify the cytokines associated with the invasive behavior of PitNETs and characterize the cytokine network and circulating immune cells in the peripheral immune microenvironment of invasive PitNETs. METHODS: Peripheral blood samples were collected from 87 patients with PitNET before transsphenoidal surgery for the resection of PitNET. Knosp grade 3 A to 4 tumors on magnetic resonance imaging (MRI) were defined as invasive PitNETs. After strict screening according to the exclusion criteria, 40 patients with invasive PitNET and 41 with noninvasive PitNET were enrolled in this study. Blood samples from 20 patients with invasive PitNET and 21 patients with non-invasive PitNET were randomly selected for multiplex plasma cytokine analysis. In addition, 20 peripheral blood samples were collected from healthy volunteers as controls. Blood samples from the remaining 20 patients with invasive PitNET and 20 patients with non-invasive PitNET were used for peripheral blood cell subpopulation analysis. RESULTS: The expression levels of MIF, MIP-1β, RANTES, IL-9, and TNF-β were increased in the peripheral blood of patients with invasive PitNET. Patients with invasive PitNET had higher levels of CD8 T cells, CD8 memory T cells, CD8 Tregs, CD4 T cells, CD4 activated T cells, CD4 memory T cells, Tregs, and macrophages, and lower levels of natural killer (NK) cells in the peripheral blood. CONCLUSION: MIF, MIP-1β, RANTES, IL-9, and TNF-β may serve as potential biomarkers for the diagnosis of invasive PitNET. The association between circulating immune cells and the cytokine network in the peripheral immune microenvironment is associated with the invasive behavior of PitNET.
Derakhshanfar A, Iraei AE, Sharif HZ
… +5 more, Yahoo Z, Hemmatzadeh M, Aslani S, Kargar R, Mohammadi H
BMC Immunol
· 2026 Apr · PMID 42050402
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Recurrent implantation failure (RIF) remains a major barrier in assisted reproduction, and systemic immune imbalance, particularly between T helper (Th) 1 and Th2 pathways, has been implicated. We performed a systematic...Recurrent implantation failure (RIF) remains a major barrier in assisted reproduction, and systemic immune imbalance, particularly between T helper (Th) 1 and Th2 pathways, has been implicated. We performed a systematic review and meta-analysis to assess peripheral blood Th1- and Th2-related markers in RIF compared with healthy fertile (HF) and IVF-successful (IS) women. We systematically searched PubMed, Scopus, and Web of Science up to June 2025 for studies that assessed circulating Th1/Th2 cells or cytokines. Compared with HF, RIF patients showed a higher frequency of Th1(IFN-γ) cells (Standardized mean difference (SMD) = 0.37, 95% confidence interval (CI) = 0.08 to 0.66, p = 0.01), while Th2(IL-4) cells did not differ. In cytokine analyses with IS controls, IFN-γ was significantly elevated in RIF (SMD = 0.91, 95% CI = 0.19 to 1.63, p = 0.01), whereas TNF-α, IL-4, and IL-10 showed no significant differences. Among ratio outcomes, IFN-γ/IL-10 (SMD = 0.70, 95% CI = 0.40 to 1.00, p < 0.00001) and TNF-α/IL-10 (SMD = 0.40, 95% CI = 0.11 to 0.69, p = 0.006) were increased in RIF, while IL-4-based ratios were not differed significantly. Our results point to an association between Th1/Th2 imbalance and RIF. Confirmation in larger, standardized studies is needed to strengthen the evidence and determine clinical applicability.
Hepatocellular carcinoma (HCC) poses a formidable therapeutic challenge due to its high heterogeneity, frequent late-stage diagnosis, and chemoresistance. Natural killer (NK) cells are essential for immune surveillance,...Hepatocellular carcinoma (HCC) poses a formidable therapeutic challenge due to its high heterogeneity, frequent late-stage diagnosis, and chemoresistance. Natural killer (NK) cells are essential for immune surveillance, yet their quantity and function become significantly compromised during HCC progression, thereby promoting tumour immune escape. This review systematically outlines current NK cell-based immunotherapeutic strategies for HCC, including adoptive NK cell transfer, genetic engineering of NK cells, NK cell inhibitory receptor-targeted therapies, reprogramming of the immunosuppressive HCC microenvironment, cytokine-mediated enhancement of NK cell function, and traditional Chinese medicine-augmented NK cell cytotoxicity. Representing a promising immunotherapeutic paradigm, NK cell-based therapy is rapidly advancing from conventional cell infusion toward more precise modalities, including CAR-NK cells and multifunctional antibody engagers. However, the efficacy of these approaches is frequently curtailed by the immunosuppressive tumour microenvironment and tumour heterogeneity. Given the multifactorial nature of NK cell dysfunction, we highlight that rationally designed combination strategies-integrating genetic engineering, TME reprogramming, and checkpoint blockade-represent the most viable path toward durable clinical responses in HCC.
Lung cancer remains one of the most common and deadly malignancies worldwide, representing a process intimately associated with dynamic changes in the tumour immune microenvironment. The pulmonary mucosal barrier, which...Lung cancer remains one of the most common and deadly malignancies worldwide, representing a process intimately associated with dynamic changes in the tumour immune microenvironment. The pulmonary mucosal barrier, which serves as the first line of immune defence against pathogens and exogenous insults, not only restrains excessive inflammation by preserving local immune homeostasis but also actively participates in shaping the lung cancer microenvironment. Regulatory T cells (Tregs) are critical immunosuppressive cells that play a dual role in this context: they sustain immune tolerance by supporting mucosal barrier integrity and preventing autoimmunity, while concurrently mediating immunosuppression within the tumour niche to facilitate immune evasion and disease progression. Although recent years have seen considerable progress in elucidating the roles of the mucosal barrier and Tregs in lung cancer, their molecular regulatory networks and translational potential as therapeutic targets require further systematic investigation. This review synthesises current understanding of the interplay between the mucosal barrier and Tregs in the lung cancer immune microenvironment, with a focus on the functional balance between Treg-mediated immunosuppression and mucosal maintenance. Based on this, we propose an integrative conceptual framework-the "mucosal-Treg-tumor immune axis"-to reconcile the context-dependent duality of Tregs. It also evaluates current strategies and clinical prospects for targeting Tregs and associated signalling pathways in lung cancer immunotherapy, aiming to offer novel perspectives for therapeutic optimisation.
BMC Immunol
· 2026 Apr · PMID 42034968
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BACKGROUND: Bone marrow-derived cell (BMDC) transplantation is increasingly recognized as a valuable strategy in regenerative therapies. However, the data regarding the impact of BMDC transplantation on the severity of d...BACKGROUND: Bone marrow-derived cell (BMDC) transplantation is increasingly recognized as a valuable strategy in regenerative therapies. However, the data regarding the impact of BMDC transplantation on the severity of diabetes mellitus type 1 (DMT1). AIM: This study aimed to determine the effectiveness of adoptive transfer of BMDC isolated from either non-diabetic mice (nBMDC) or diabetic mice (dBMDC) in the treatment of a DMT1 mouse model. METHODS: Male Swiss albino mice underwent a 16-hour fasting period, followed by administration of streptozotocin (STZ) at a dose of 40 mg/kg body weight for five days to induce DMT1. After 14 days, diabetic mice were divided into four groups. The first group served as a diabetic control and received sodium citrate buffer, while the remaining three groups were treated for two weeks with one of the following: subcutaneous (s.c.) administration of insulin (8 U/kg/day), intravenous (i.v.) inoculation of nBMDCs (1 × 106 cells/mouse/once), or i.v. injections of dBMDC (1 × 106 cells/mouse/once). RESULTS: STZ-induced DMT1 mice treated with either nBMDC or dBMDC exhibited a noticeable increase in the expression of CD4+ T lymphocytes, CD8+ T lymphocytes, and NK lymphocytes, myeloid granulocytic neutrophil (CD11b+/Ly-6G+ cells), monocytic macrophage (CD11b+/Ly-6G− cells), and monocytic CD11b+/Ly-6G− cells. Additionally, there was a marked reduction in the percentages of CD25+ T cells, Foxp3+ cells, regulatory T cells (Tregs), CD25+/Foxp3+ cells, Treg CD25+/Foxp3− cells, Treg CD4+/CD25+ cells, and Treg CD4+/CD25− cells within the myeloid cell population in the spleen. The therapeutic efficacy of BMDC as an anti-diabetic therapy was further supported by a significant reduction in the proportion of early and late apoptosis in splenic leukocytes, accompanied by a slight increase in necrosis in STZ-induced DMT1 mice receiving either nBMDC or dBMDC. CONCLUSION: In summary, adoptive transfer of BMDCs exerts significant immunomodulatory and anti-apoptotic effects on pancreatic β cells, which are beneficial for pancreatic islets in DMT1 mice. Clinical studies are warranted to evaluate the safety and effectiveness of the adoptive transfer of BMDCs as a potential therapy for autoimmune DMT1.
Plaza-Florido A, Carrera-Bastos P, Pérez-Prieto I
… +7 more, Fiuza-Luces C, Radom-Aizik S, Del Pozo Cruz B, Franceschi C, López-Soto A, López-Otín C, Lucia A
Centenarians - individuals aged 100 years or older - constitute a biologically distinct human population that achieves exceptional longevity while frequently retaining functional independence and avoiding major age-relat...Centenarians - individuals aged 100 years or older - constitute a biologically distinct human population that achieves exceptional longevity while frequently retaining functional independence and avoiding major age-related diseases or postponing their onset. Despite their advanced age, many centenarians show relatively preserved immune function and resistance to conditions linked to immunosenescence and chronic low-grade inflammation (inflammageing). These features are especially pronounced in semi-supercentenarians (105-109 years) and supercentenarians (≥110 years), whose immune profiles often resemble those of much younger individuals. In this Review, we explore how centenarians modulate key hallmarks of immune ageing across innate and adaptive immune compartments. We discuss evidence that they limit the pathological effects of inflammageing, potentially through reduced NLRP3 inflammasome activation, enhanced autophagy and a tempered senescence-associated secretory phenotype. Omics studies further reveal transcriptomic, epigenetic and microbial signatures consistent with preserved immune function, including youth-like gene expression patterns in circulating immune cells and beneficial shifts in gut microbiome composition. Together, these findings suggest that centenarians achieve longevity through coordinated adaptations that maintain immune homeostasis and disease resistance and may inform strategies to enhance healthspan in ageing societies.
Leishmania are intracellular protozoan parasites transmitted to humans by the bite of infected phlebotomine sand flies. Human infection is often asymptomatic but can develop into a broad spectrum of clinical diseases, co...Leishmania are intracellular protozoan parasites transmitted to humans by the bite of infected phlebotomine sand flies. Human infection is often asymptomatic but can develop into a broad spectrum of clinical diseases, collectively termed the leishmaniases. The underlying immunological features associated with asymptomatic infection and the varying clinical forms of disease have been extensively studied in pre-clinical models (including rodents, dogs and primates), as well as in human populations. Here, concentrating on data derived from human studies, we review the current understanding of how diverse lymphocyte-mediated immune responses drive the human disease spectrum seen following Leishmania infection.
Cutaneous melanoma (CM) is an aggressive cancer where early intervention is crucial, but the prognostic role and mechanisms of ubiquitination-related genes (URGs) in immune regulation remain unclear. This study aimed to...Cutaneous melanoma (CM) is an aggressive cancer where early intervention is crucial, but the prognostic role and mechanisms of ubiquitination-related genes (URGs) in immune regulation remain unclear. This study aimed to develop a URG-based prognostic signature and explore its relationship with immune modulation in CM. We integrated single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data, identifying prognostic URGs through univariate and multivariate Cox regression. A six-gene signature (UBE2L6, SPSB1, PSMB9, PSMB10, RNF213 and ATXN3) was established and validated. The signature effectively stratified patients into high- and low-risk groups, with significant survival differences. Pathway analysis revealed immune-related processes, such as 'cytokine-cytokine receptor interaction' and 'antigen processing and presentation', enriched in the low-risk group. Immune cell infiltration analysis demonstrated significant differences in the abundance of 12 immune cell types between risk groups. Notably, PSMB9 expression was positively correlated with CD8 T cell abundance (r = 0.64, p < 0.05). scRNA-seq analysis highlighted T cells as a key cell type, with all six prognostic genes showing dynamic expression changes during T cell differentiation. Our findings suggest that URGs influence CM prognosis by modulating the immune microenvironment, offering new insights for immunotherapeutic strategies.
Monocytes and macrophages are versatile immune sentinels that are present in nearly all tissues, where they continually adapt to local cues. In cancer, their functions are context-dependent - often linked to tumour growt...Monocytes and macrophages are versatile immune sentinels that are present in nearly all tissues, where they continually adapt to local cues. In cancer, their functions are context-dependent - often linked to tumour growth and poor prognosis but also capable of driving potent antitumour immunity. To explain this dichotomy, we frame cancer cells as 'infectious self', having both pathogen-like and self-like features. In turn, monocytes and macrophages adopt modular programmes across primary and metastatic tumour sites - as well as along haematogenous, lymphatic and transcoelomic routes of dissemination - that are shaped by oncogenic lesions, cancer cell differentiation states, tissue perturbations and organism-level variables. These cells are promising yet challenging therapeutic targets. Opportunities include blocking the recruitment, differentiation and scavenging activity of pro-tumour monocytes and macrophages; activating pattern recognition receptor signalling pathways and lymphocyte help; inducing cancer cell phagocytosis; and rewiring key intracellular signalling nodes. Emerging cellular and gene-based approaches - such as chimeric receptor engineering and in vivo target delivery - further expand this toolkit and underscore the potential to reprogramme monocyte and macrophage responses for durable control of solid tumours.
Tissue-resident macrophages are crucial sentinel cells of the innate immune system that sense nutrient fluctuations and orchestrate adaptive responses to support steady-state metabolic homeostasis. When dysregulated, the...Tissue-resident macrophages are crucial sentinel cells of the innate immune system that sense nutrient fluctuations and orchestrate adaptive responses to support steady-state metabolic homeostasis. When dysregulated, these cells have major roles in the pathogenesis of numerous diseases, including obesity-associated metabolic diseases such as type 2 diabetes, metabolic dysfunction-associated fatty liver disease and atherosclerotic cardiovascular disease. Cellular and phenotypic remodelling of macrophage populations in response to metabolic alterations linked to obesity perturbs homeostatic interactions and promotes low-grade sterile tissue inflammation, which propagates tissue dysfunction. Much of the seminal initial work in the field of 'immunometabolism' explored the role of metabolic pathways in the regulation of distinct immune cell types. More recently, however, it has become appreciated that intermediary metabolites can function as signals that regulate macrophages at the level of the whole tissue or organism. As we discuss here, recent work has identified intermediary metabolites such as lactate, succinate and itaconate, and nutrients including glucose, amino acids and free fatty acids, as crucial regulatory signals that control macrophage function in obesity and metabolic disease.
BMC Immunol
· 2026 Apr · PMID 41975260
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BACKGROUND: Childhood pneumonia (CP) represents a leading cause of pediatric mortality globally. Consequently, prompt diagnosis of CP is of great significance for its treatment and prognosis. OBJECTIVE: The objective of...BACKGROUND: Childhood pneumonia (CP) represents a leading cause of pediatric mortality globally. Consequently, prompt diagnosis of CP is of great significance for its treatment and prognosis. OBJECTIVE: The objective of this study is to investigate the clinical significance of miR-369-5p in CP and its underlying mechanism. METHODS: This study enrolled clinical data from 69 CP patients and 60 healthy individuals. Through binary logistic analysis, ROC analysis, and Kaplan-Meier (KM) analysis, the diagnostic and prognostic utility of miR-369-5p for CP was determined. The RT-qPCR experiment was used to detect the expression levels of miR-369-5p, polymeric immunoglobulin receptor (PIGR), and inflammatory cytokines. The study used LPS (Lipopolysaccharide) to induce WI-38 cells to establish a pneumonia cell model for in vitro cell experiments and used the kit to detect the oxidative stress indicators. The cell proliferation and apoptosis were detected through CCK8 (Cell Counting Kit-8) and flow cytometry assays. The target genes of miR-369-5p were predicted using TargetScan database and subsequently validated via dual luciferase reporter assays. Pearson analysis revealed the correlation between miR-369-5p and PIGR. RESULTS: MiR-369-5p was markedly overexpressed in CP, serving as a diagnostic biomarker for CP, as well as being associated with a poor prognosis. LPS induction in WI-38 cells triggered miR-369-5p upregulation, which coincided with enhanced levels of inflammation, oxidative stress indicators and apoptosis, and a decline in proliferation capacity. PIGR was confirmed as a downstream target of miR-369-5p. Silencing miR-369-5p could lead to increased expression of PIGR, decreased expression of inflammatory factors and oxidative stress indicators, and enhanced cell activity. Meanwhile, inhibition of PIGR could weaken the effect of inhibiting miR-369-5p. CONCLUSION: Upregulated serum miR-369-5p serves as a promising non-invasive biomarker for the diagnosis and prognosis of CP. Inhibiting miR-369-5p can ameliorates the condition of CP by targeting PIGR.
Targeting Toll like receptors (TLRs) signalling represents a powerful approach to re-calibrate host immunity against intracellular pathogens. Among these, dual TLR7/8 agonists uniquely bridge innate and adaptive immune r...Targeting Toll like receptors (TLRs) signalling represents a powerful approach to re-calibrate host immunity against intracellular pathogens. Among these, dual TLR7/8 agonists uniquely bridge innate and adaptive immune response through NF-κβ-associated cytokine programming and activation of innate effector pathways. Here we, identify and characterise a dihydroxyimidazoquinoline-based TLR7/8 agonist as a potent immunomodulatory adjuvant that enhances the efficacy of heat-killed Leishmania donovani antigen vaccine in BALB/c mice. Comparative immunisation with escalating adjuvant doses (10, 25 and 50 μg) demonstrated a robust, dose-dependent reduction in splenic parasite burden, accompanied by sustained elevation of Th1 cytokine (IFN-γ and TNF-α) and suppression of Th2-associated cytokine (IL-10 and IL-13) up to 16-week post-challenge. Enhanced iNOS and NF-κβ gene expression, together with elevated ROS and NO production, indicated activation of host effector pathways underlying parasite clearance. Flow cytometric analysis revealed persistent expansion of both CD4 and CD8 T cell subsets in the high-dose groups supporting durable adaptive immunity. The dual TLR7/8 activity of this compound mediated broad and sustained immunoregulatory signalling that surpassed resiquimod in magnitude and persistence. Collectively, this study delineated a mechanistic framework for TLR7/8 driven immunoregulation and establishes dihydroxyimidazoquinoline as a next-generation adjuvant for rational, host-directed vaccine design against intracellular pathogens such as L. donovani .
Cytokines are essential mediators of immune functions and regulate many other biological processes, ranging from fetal development to ageing. Dysregulation of cytokine responses can substantially increase the risk of dis...Cytokines are essential mediators of immune functions and regulate many other biological processes, ranging from fetal development to ageing. Dysregulation of cytokine responses can substantially increase the risk of disease and so their activity requires tight control. The formation of cytokine homodimers, heterodimers and multimers has evolved as a versatile mechanism to regulate cytokine biology, in which multimerization can enable or attenuate their activity, diversify signalling outcomes and drive signalling bias. Here, we discuss the structure-function implications of cytokine multimerization for type I cytokines (for example, the IL-6 and IL-12 cytokine families), type II cytokines (for example, the IL-10 and interferon families), cytokines that signal through immunoglobulin-family receptors (for example, the IL-1 and M-CSF families) and also for the IL-17, TNF and TGFβ cytokine families. We highlight the influence of multimerization on cytokine activity and receptor engagement, as well as the relevance of cytokine multimerization for disease development and the resulting therapeutic opportunities.
The liver, a key metabolic organ, has a central role in maintaining systemic homeostasis but is vulnerable to numerous diseases. Its metabolic functions are mainly carried out by hepatocytes; however, the liver also harb...The liver, a key metabolic organ, has a central role in maintaining systemic homeostasis but is vulnerable to numerous diseases. Its metabolic functions are mainly carried out by hepatocytes; however, the liver also harbours diverse non-parenchymal cell populations, including immune cells. Among these, Kupffer cells, the resident macrophages of the liver, are critical modulators of liver function and immunity. Emerging research highlights their dynamic roles throughout life, from maintaining tissue homeostasis to shaping the balance between immune tolerance and activation in adulthood. Kupffer cells are located in liver sinusoids, where they act as frontline defenders, clearing pathogens and cellular debris from the circulation. Beyond their established phagocytic and immune regulatory functions, Kupffer cells influence metabolic processes, tissue repair and oncogenesis. Moreover, they shape the response of the liver to metabolic disorders such as metabolic dysfunction-associated steatohepatitis, infections and malignancies, including hepatocellular carcinoma. Here we explore Kupffer cell biology, focusing on the development, heterogeneity and multifaceted roles of these cells in liver health and disease. We further discuss how advances in imaging, transcriptomics and macrophage-targeted therapies can inform future strategies to combat liver-associated health challenges.