The annual ImmunoRad Conference has established itself as a recurrent occasion to explore the possibility of combining radiation therapy (RT) and immunotherapy (IT) for clinical cancer management. Bringing together a number of preclinical and clinical leaders in the fields of radiation oncology, immuno-oncology and IT, this annual event fosters indeed essential conversations and fruitful exchanges on how to address existing challenges to expand the therapeutic value of RT-IT combinations. The 8th edition of the ImmunoRad Conference, which has been held in October 2024 at the Weill Cornell Medical College of New York City, highlighted exciting preclinical and clinical advances at the interface between RT and IT, setting the stage for extra progress toward extended benefits for patients with an increasing variety of tumor types. Here, we critically summarize the lines of investigation that have been discussed at the occasion of the 8th Annual ImmunoRad Conference.

Multiple sclerosis (MS) is an autoimmune disease characterized by the loss of oligodendrocytes (OLs) and axon demyelination in the central nervous system. Most therapeutic agents focus on regulating the immune response by suppressing autoimmune reactions. Therefore, developing therapeutic agents that promote remyelination by OLs at disease sites that have already undergone demyelination is necessary. In this study, we generated a new transgenic zebrafish with high efficiency for OL ablation and established a high-throughput screening (HTS)-based platform to identify therapeutic candidates that promote remyelination. Next, we screened a library of kinase inhibitors and identified one candidate, a transforming growth factor-β receptor I (TGF-βRI) kinase inhibitor. Treatment with this kinase inhibitor rapidly recruited microglia to induce clearance of myelin debris, early after OL removal. It also increased the proliferation of OL progenitor cells in demyelinating zebrafish larvae, resulting in restored OL numbers and reduced locomotor activity. Based on these results, we expect our HTS-based platform, along with our newly developed zebrafish model, to be very useful for identifying therapeutic agents that promote remyelination. Furthermore, since the candidate TGF-βRI kinase inhibitor identified in this study restored the phenotype following demyelination, we suggest that TGF-βRI kinase may potentially be a therapeutic target for the treatment of demyelinating diseases.

Osteogenesis imperfecta (OI), also called brittle bone disease, is a genetic osteodysplasia characterized by a defect in type 1 collagen. Often diagnosed in infancy or early childhood, young patients are affected by frequent fractures. Osteogenesis imperfecta was first named almost 200 yr ago, yet there are still no FDA-approved treatments for OI, and existing treatments target only the skeletal defects of the disease. In this review, we briefly examine current treatments and ongoing clinical trials. Then, by analyzing OI with an osteoimmunological perspective, we have compiled evidence that OI has an autoimmune component. This autoimmune component of OI remains unconsidered, even though an immunology-based therapy has shown promise in treating OI. Acknowledging an autoimmune component of OI is critical to understanding its mechanisms and allowing for the development of more efficacious treatments and novel immunotherapies. Considering the existing literature and the growing impact of immunotherapeutic therapies in cancer and other autoimmune diseases, we believe it may be time to rethink the immune aspects of this genetic disorder and develop novel immunomodulating strategies to improve the quality of life for OI patients.

While Chimeric Antigen Receptor (CAR) T cell therapy may result in durable remissions in recurrent large B cell lymphoma, persistence is limited and the mechanisms underlying long-term response are not fully elucidated. Using longitudinal single-cell immunoprofiling, here we compare the immune landscape in durable remission versus early relapse patients following CD19 CAR T cell infusion in the NCT02348216 (ZUMA-1) trial. Four weeks post-infusion, both cohorts demonstrate low circulating CAR T cells. We observe that long-term remission is associated with elevated native cytotoxic and proinflammatory effector cells, and post-infusion clonotypic expansion of effector memory T cells. Conversely, early relapse is associated with impaired NK cell cytotoxicity and elevated immunoregulatory cells, potentially dampening native T cell activation. Thus, we suggest that durable remission to CAR T is associated with a distinct T cell signature and pattern of clonotypic expansion within the native T cell compartment post-therapy, consistent with their contribution to the maintenance of response.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19. The accessory proteins of SARS-CoV-2 have been reported to attune host immune responses and viral pathogenicity. We have studied the effect of SARS-CoV-2 accessory proteins ORF3a and ORF6 on the expression pattern of miRNAs and their impact on cell signaling pathways in human lung epithelial cells.

The miRNA expression profiling of human lung epithelial cells revealed a subset of 14 and 19 differentially expressed miRNAs (DEMs) in response to SARS-CoV-2 ORF3a and ORF6, respectively. Target prediction tools and subsequent bioinformatic analysis revealed the involvement of DEMs in key signaling pathways like PI3K/AKT, TNF, MAPK, TGF-β, and NF-κB, as a bystander effect of SARS-CoV-2 ORF3a and ORF6. The target genes were validated using real-time PCR and immunoblotting techniques. The results demonstrate that SARS-CoV-2 ORF3a and ORF6 exploit host cellular miRNAs such as hsa-miR-101-3p, hsa-miR-4455, hsa-miR-10b-5p, hsa-miR-940, and hsa-miR-4483, etc. to modulate the key cellular signaling pathways like NF-κB, TGF-β, Ras, IL-17, MAPK, and TNF signaling pathways.

The present study demonstrates that SARS-CoV-2 ORF3a and ORF6 modulate the miRNA expression pattern in human lung epithelial cells. ORF3a exploits miRNAs to trigger a pro-inflammatory response, while ORF6 antagonizes IFN signaling via miRNA dysregulations to help SARS-CoV-2 in evading the host's immune response.

The mechanisms underlying the formation and rupture of intracranial aneurysms remain unclear. Rupture of the aneurysmal wall causes subarachnoid hemorrhage, with a mortality rate of 35-50%. Literature suggests that rupture is associated with the remodeling of the aneurysmal wall, including endothelial cell damage, smooth muscle cells (SMCs) proliferation, and inflammatory cell infiltration, particularly macrophages. Transforming growth factor β (TGF-β) is a multifunctional factor that plays a diverse role in cell growth and differentiation. It is crucial for strengthening vessel walls during angiogenesis and also regulates the proliferation of SMCs, indicating the potential involvement of TGF-β signaling in the pathogenesis and development of cerebral aneurysms. This review examines the complex role of TGF-β, its receptors, and signaling pathways in cerebral aneurysm formation and progression. Understanding the molecular mechanisms of TGF-β signaling in aneurysm development is vital for identifying potential therapeutic targets to prevent aneurysm rupture. Further research is necessary to fully elucidate the role of TGF-β in aneurysm pathophysiology, which could lead to the development of novel therapeutic strategies for aneurysm prevention and management, particularly in preventing subarachnoid hemorrhage.

RNA modifications are pivotal regulators of gene expression, significantly influencing immune responses by modulating the stability and translation of mRNAs encoding key immunoregulatory ligands and receptors. Among these modifications, N6-methyladenosine (m6A) is the most abundant and well-characterized, orchestrating immune evasion, T-cell exhaustion, and cytokine production by dynamically regulating transcripts such as PD-L1, IFN-γ, and TGF-β. These modifications critically impact the function and availability of proteins essential for maintaining immune homeostasis and shaping adaptive immune responses. This review comprehensively examines established and emerging roles of mRNA modifications in regulating immunoregulatory signaling, including co-inhibitory and co-stimulatory molecules, chemokines, cytokines, and transforming growth factor-β. We highlight how m6A writers, erasers, and readers finely regulate immune checkpoints and inflammatory pathways across cancer, infection, and autoimmune diseases. Furthermore, the review provides a critical analysis of current discrepancies in the field, emphasizing factors contributing to inconsistencies and offering insights into the complex nature of epigenetic regulation. Challenges and limitations in this rapidly evolving area are also discussed. Advancing detection technologies and developing specific inhibitors targeting RNA-modifying proteins will be crucial for precisely modulating immune responses, paving the way for innovations in precision medicine and immunotherapy.

Guillain‒Barré syndrome (GBS) is an immune-mediated peripheral neuropathy in which inflammatory cells and cytokines participate. The JAK-STAT signaling pathway is a major pathway involved in cytokine signal transduction, but the role of this pathway in GBS is not clear. AG490 is a tyrosine kinase inhibitor that specifically inhibits JAK2 activity and downregulates STAT3 phosphorylation. The aim of this study was to investigate the function of the JAK2/STAT3 pathway in a rat model of experimental autoimmune neuritis (EAN).

Lewis rats were divided into three groups: the control, the EAN, and the AG490 groups. The EAN and AG490 groups were immunized with P2 peptide to create the EAN models, while the control group received an equal volume of vehicle solution without P2 peptide. Starting from Day 5 post-immunization (PI), the AG490 group was administered AG490 (10 mg/kg) every other day, while the control and EAN groups received an equal volume of vehicle solution without AG490. All rats were weighed and evaluated according to the EAN function score (1-10) by two investigators. Rats were sacrificed on Day 16 PI, and the sciatic nerves were examined by light microscopy, indirect immunohistochemistry, and western blotting.

AG490-treated rats had improved clinical scores compared with those of EAN rats. Hematoxylin and eosin (H&E) and CD45 staining showed significant inflammatory infiltration of the sciatic nerve in the EAN group compared with the control group, and demonstrated reduced inflammatory infiltration in the AG490 group. Luxol fast blue (LFB) staining showed a reduction of myelin loss in the AG490 group compared with the EAN group. The levels of TGF-β1, IFN-γ, and IL-6 increased in the EAN group and showed a significant decrease in rats treated with AG490. The JAK2-STAT3 signaling pathway was activated in EAN rats, and the AG490 group showed decreased expression levels of JAK2, p-JAK2, and p-STAT3 compared with those of the EAN group. Immunofluorescence also showed a decrease in the levels of p-JAK2 and p-STAT3 in the sciatic nerve of EAN rats.

The JAK2/STAT3 signaling pathway is involved in the pathogenesis of EAN, and inhibition of this pathway can reduce the inflammatory response in EAN rats. Despite the limitations in extrapolating EAN findings to human GBS, this study provided new insights into the pathogenesis and potential therapeutic targets of human GBS.

TGF-β is a pleiotropic cytokine with both stimulatory and inhibitory effects on immune cells, depending on the microenvironmental context. It targets mast cells (MCs) in different physio-pathological conditions, such as inflammation and cancer. Besides acting as a potent chemoattractant for MCs, TGF-β regulates many other aspects of MCs' physiology, including the secretion of many regulatory molecules. MCs secrete a variety of mediators, either pre-formed or newly synthesized, upon appropriate stimulation. CCL-2 chemokine and TNF cytokine act as potent chemoattractants for several immune cells and participate in the initiation of inflammatory responses by recruiting them to injured tissues. TGF-β regulates CCL-2 and TNF secretion in different cell types and under distinct cellular contexts. Here, we report that the treatment with TGF-β alone induces the secretion of both pre-formed and newly synthesized CCL-2 in the rat RBL-2H3 mast cells but not in mouse bone marrow-derived mast cells (BMMCs). TGF-β-induced CCL-2 secretion depends on rapid rearrangements of the actin cytoskeleton and, remarkably, on the early secretion of soluble TNF that triggers an autocrine TNF signaling. In conclusion, we found cooperation between TGF-β and TNF signaling pathways to promote the secretion of CCL-2 chemokine by MCs in a cell-context specific manner.

Helminth parasites have evolved sophisticated methods for manipulating the host immune response to ensure long-term survival in their chosen niche, for example, by secreting products that interfere with the host cytokine network. Studies on the secretions of Heligmosomoides polygyrus have identified a family of transforming growth factor-β (TGF-β) mimics (TGMs), which bear no primary amino acid sequence similarity to mammalian TGF-β, but functionally replicate or antagonise TGF-β effects in restricted cell types. The prototypic member, TGM1, induces in vitro differentiation of Foxp3+ T regulatory cells and attenuates airway allergic and intestinal inflammation in animal models. TGM1 is one of a family of ten TGM proteins expressed by H. polygyrus. It is a five-domain modular protein in which domains 1-2 bind TGFBR1, and domain 3 binds TGFBR2; domains 4-5 increase its potency by binding a co-receptor, CD44, highly expressed on immune cells. Domains 4-5 are more diverse in other TGMs, which bind co-receptors on cells such as fibroblasts. One variant, TGM6, lacks domains 1-2 and hence cannot transduce a signal but binds TGFBR2 through domain 3 and a co-receptor expressed on fibroblasts through domains 4-5 and blocks TGF-β signalling in fibroblasts and epithelial cells; T cells do not express the co-receptor and are not inhibited by TGM6. Hence, different family members have evolved to act as agonists or antagonists on various cell types. TGMs, which function by molecularly mimicking binding of the host cytokine to the host TGF-β receptors, are examples of highly evolved immunomodulators from parasites, including those that block interleukin (IL)-13 and IL-33 signalling, modulate macrophage and dendritic cell responses and modify host cell metabolism. The emerging panoply and potency of helminth evasion molecules illustrates the range of strategies in play to maintain long-term infections in the mammalian host.

Vaccinia virus (VACV) and mpox virus (MPXV) belong to the orthopoxvirus genus and share high genetic similarity, making VACV widely used in the mpox pandemic. CAST/EiJ mice have been widely used for studying orthopoxvirus infection. However, the histopathological features of CAST/EiJ mice with mpox virus (MPXV) and vaccinia virus (VACV) infections have not been fully elucidated.

Four group of CAST/EiJ mice were challenged with low-dose VACV (103 PFU, VACV-L), high-dose VACV (106 PFU, VACV-H), MPXV (106 PFU) or PBS via intraperitoneal route, and the disease signs and body weight were monitored daily. Subsequently, viral loads and titers in the blood and spleen of CAST/EiJ mice were analyzed via qPCR and TCID50 assay. Finally, the spleen samples were analyzed for histopathological, immunohistochemical and RNA-seq.

Herein, we found that VACV-L and MPXV caused splenomegaly via the intraperitoneal route, whereas VACV-H caused rapid lethality with limited splenomegaly. Transcriptome analysis from spleen revealed significant differences in gene expression between VACV-L and VACV-H groups, but the differentially expressed genes induced by splenomegaly between VACV-L and MPXV groups were highly similar. Furthermore, pathway enrichment analysis demonstrated that the VACV-L, VACV-H, and MPXV groups were all associated with the calcium, MAPK, and PI3K-Akt signaling pathway. Compared to the lethal infection observed in VACV-H group, the splenomegaly in the VACV-L and MPXV groups was characterized by extramedullary hematopoiesis and increased macrophages infiltration in the red pulp. Transcriptome analysis of the spleen demonstrated that the Wnt, tumor necrosis factor (TNF), and transforming growth factor β (TGF-β) signaling pathways may promote splenomegaly by modulating granulocyte infiltration and inflammatory responses. Compared to VACV-L group, the limited splenomegaly but lethality in VACV-H-infected mice might be associated with extensive splenic necrosis, diffuse congestion, and hemorrhage in the red pulp, as well as changes in the cGMP-PKG, Ras signaling, and Fc gamma R-mediated phagocytosis pathways.

Our findings systematically compared the pathogenicity of VACV and MPXV in CAST/EiJ mice, incorporating splenic transcriptome analysis to provide insights into the potential molecular mechanism behind orthopoxvirus-induced splenomegaly in CAST/EiJ mice.

P Natural killer (NK) cells function as crucial effectors in the innate immune response against tumors. Nevertheless, NK cell senescence, characterized by phenotypic and functional changes, substantially compromises their antitumor immune response. This review provides a comprehensive summary of the molecular mechanisms governing NK cell senescence and its implications for cancer immunotherapy. We propose a refined definition of NK cell senescence based on distinct biomarkers, including elevated CD57 expression, reduced cytotoxicity, and altered cytokine secretion. Moreover, we investigate the complex interactions between the tumor microenvironment (TME) and NK cell senescence, highlighting the influence of chronic inflammation, immunosuppressive cytokines, and persistent tumor antigenic stimulation. Additionally, this review underscores the potential utility of senescent NK cells as biomarkers for assessing antitumor efficacy and examines the adverse effects of NK cell senescence on cancer immunotherapy. Lastly, we summarize current approaches to mitigate NK cell senescence, such as gene editing techniques and cytokine modulation, which may enhance the efficacy of NK cell-based immunotherapies. By establishing a comprehensive framework for understanding NK cell senescence within the TME, this review aims to guide future research and the development of innovative therapeutic strategies targeting senescent NK cells to improve cancer immunotherapy outcomes.

In humans, aging is an inevitable consequence of diminished growth processes after reaching maturity. The high order of biomolecules in cells and tissues is continuously disturbed by numerous physical and chemical destructive impacts. Host-derived oxidant-based cytotoxic agents (reactive species, transition free metal ions, and free heme) contribute considerably to this damage. These agents are under the control of immediately acting antagonizing principles, which are important to ensure cell and tissue homeostasis. In this review, I apply the concept of host-derived cytotoxic agents and their interplay with antagonizing principles to the aging process. During aging, energy metabolism and the supply of tissues with dioxygen and nutrients are increasingly disturbed. In addition, a chronic inflammatory state develops, a condition known as inflammaging. The balance between oxidant-based cytotoxic agents and protective mechanisms is analyzed depending on age-based physiological alterations in ATP production. Disturbances in this balance are associated with the development of age-related diseases and comorbidities. An enhanced production of reactive species from dysfunctional mitochondria, alterations in cellular redox homeostasis, and adaptations to hypoxia are highlighted. Examples of how disturbances between oxidant-based cytotoxic agents and antagonizing principles contribute to the pathogenesis of diseases in persons of advanced age are given.

The accumulation of senescent cells within tissues promotes the aging process by remodelling the functions of the immune system. For many years, it has been known that senescent cells secrete pro-inflammatory cytokines and chemokines, a phenotype called the senescence-associated secretory phenotype (SASP). Chemokines and colony-stimulating factors stimulate myelopoiesis and recruit myeloid cells into aging tissues. Interestingly, recent studies have demonstrated that senescent cells are not only secretory but they also express an increased level of ligand proteins for many inhibitory immune checkpoint receptors. These ligands represent "don't eat me" markers in senescent cells and moreover, they are able to induce an exhaustion of many immune cells, such as surveying natural killer (NK) cells, cytotoxic CD8+ T cells, and macrophages. The programmed cell death protein-1 (PD-1) and its ligand PD-L1 represent the best known inhibitory immune checkpoint pathway. Importantly, the activation of inhibitory checkpoint receptors, e.g., in chronic inflammatory states, can also induce certain immune cells to differentiate toward their immunosuppressive phenotype. This can be observed in myeloid derived suppressor cells (MDSC), tissue regulatory T cells (Treg), and M2 macrophages. Conversely, these immunosuppressive cells stimulate in senescent cells the expression of many ligand proteins for inhibitory checkpoint receptors. Paradoxically, senescent cells not only promote the pro-inflammatory state but they maintain it at a low-grade level by expressing ligands for inhibitory immune checkpoint receptors. Thus, the cooperation between senescent cells and immunosuppressive cells enhances the senescence state of immune cells, i.e., immune senescence/exhaustion, and cellular senescence within tissues via bystander effects.

Transforming growth factor-β (TGF-β) plays a complex role in lung cancer pathophysiology, initially acting as a tumor suppressor by inhibiting early-stage tumor growth. However, its role evolves in the advanced stages of the disease, where it contributes to tumor progression not by directly promoting cell proliferation but by enhancing epithelial-mesenchymal transition (EMT) and creating a conducive tumor microenvironment. While EMT is typically associated with enhanced migratory and invasive capabilities rather than proliferation per se, TGF-β's influence on this process facilitates the complex dynamics of tumor metastasis. Additionally, TGF-β impacts the tumor microenvironment by interacting with immune cells, a process influenced by genetic and epigenetic changes within tumor cells. This interaction highlights its role in immune evasion and chemoresistance, further complicating lung cancer therapy. This review provides a critical overview of recent findings on TGF-β's involvement in lung cancer, its contribution to chemoresistance, and its modulation of the immune response. Despite the considerable challenges encountered in clinical trials and the development of new treatments targeting the TGF-β pathway, this review highlights the necessity for continued, in-depth investigation into the roles of TGF-β. A deeper comprehension of these roles may lead to novel, targeted therapies for lung cancer. Despite the intricate behavior of TGF-β signaling in tumors and previous challenges, further research could yield innovative treatment strategies.

The tumor microenvironment (TME) is a pro-cancerous niche harboring immunosuppressive factors that are secreted by cancer cells and the surrounding cancer-supportive tissue, such as kynurenine, prostaglandin E2 and transforming growth factor β (TGFβ). These factors dampen the activity of cytotoxic lymphocytes like natural killer (NK) cells, allowing evasion of immune cell-mediated killing. To identify small molecules that counteract the immunosuppressive effect of the TME and restore NK cell-mediated cytotoxicity, we developed a phenotypic co-culture assay of cancer cells and primary lymphocytes suitable for medium-throughput screening. We discovered small molecules that restore NK cell-mediated cytotoxicity through diverse mechanisms. The potent TGFβ type I receptor (TGFβR-1) inhibitor, RepSox, stood out as superior to other TGFβR-1 inhibitors due to its ability to abolish the effects of both inhibitory factors used in our setup. This mode of action goes beyond TGFβR-1 inhibition and is related to the simultaneous abrogation of cyclooxygenase 1 (COX1) activity.

On-pump coronary artery bypass grafting (CABG) triggers inflammatory responses as a result of surgical stress and extracorporeal circulation, which affect platelet and leukocyte activation while enhancing their intimate crosstalk. Given this, the study presented here aimed to investigate platelet-T cell interaction after CABG focusing on the changes in immunomodulatory subtypes of regulatory T Cells.

Blood samples were obtained from twenty patients undergoing on-pump CABG at 5 different time points of 24 h before, immediately, 2 h, 24 h, and one week after surgery. Total leukocyte and lymphocyte counts were determined using an automatic cell counter. Platelet P-selectin expression, frequencies of CD4+ and CD8+ T cells, platelet-T cell aggregates (PTCAs), and regulatory T cells derived from CD4+ (T4reg) and CD8+ (T8reg) cells, were assessed by flow cytometry.

A significant increase in total leukocyte count occurred immediately after CABG, whereas, conversely, lymphocyte and CD4+ T cells but not CD8+ T cells decreased 2 h after surgery. However, all these changes returned to pre-CABG baseline levels within a week. Platelet P-selectin expression increased immediately after surgery, followed by a two-hour delay after PTCA, and both returned to baseline after one week. T4regs and T8regs showed a similar increase and decrease trend, where T8regs but not T4regs returned to baseline one week after surgery.

CABG surgery induces an inflammatory response that activates platelets and enhances P-selectin expression, facilitating PTCA formation. This mechanism is critical for the dynamics and differentiation of T cells, which play an essential role in post-CABG modulation of immune responses.

Tuberculosis (TB) remains a major global health challenge, particularly in the context of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb). Host-directed therapies (HDTs) have been proposed as adjunctive therapy to enhance immune control of infection. Recently, one such HDT, pharmacologic modulation of myeloid-derived suppressor cells (MDSCs), has been proposed to treat MDR-TB. While MDSCs have been well characterized in cancer, their role in TB pathogenesis remains unclear. To investigate whether MDSCs or other myeloid suppressor populations contribute to TB granuloma microenvironments (GME), we performed spatial transcriptional profiling and single-cell immunophenotyping on eighty-four granulomas in lung specimens from three individuals with active disease. Granulomas were histologically classified based on H&E staining, and transcriptional signatures were compared across regions of interest (ROIs) at different states of granuloma maturation. Our analysis revealed that immune suppression within granuloma was not primarily driven by classical MDSCs but rather by multiple myeloid cell subsets, including dendritic cells expressing indoleamine 2,3 dioxygenase-1 expressing (IDO1+ DCs). IDO1+ DCs were the most frequently observed suppressive myeloid cells, particularly in cellular regions, and their spatial proximity to activated T cells suggested localized immunosuppression. Importantly, granulomas at different stages contained distinct proportions of suppressor myeloid cells, with necrotic and cellular regions showing different myeloid phenotypes that may influence granuloma progression. Gene set enrichment analysis (GSEA) further indicated that elevated IDO1 expression was associated with a complex immune response that balanced suppressive signaling, immune activation, and cellular metabolism. These findings suggest that classical MDSCs, as defined in tumor microenvironments, likely play a minor role in TB, whereas IDO1+ DCs may be key regulators of immune suppression in granulomas influencing local Mtb control in infected lung. A deeper understanding of the role of IDO1+ suppressive myeloid cells in TB granulomas is essential to assessing their potential as therapeutic targets in TB treatment.

The body's innate immune system plays a pivotal role in identifying and eliminating cancer cells. However, as the immune system ages, its functionality can deteriorate, becoming dysfunctional, inefficient, or even inactive-a condition referred to as immunosenescence. This decline significantly increases the risk of malignancies. While the pro-cancer effects of T-cell aging have been widely explored, there remains a notable gap in the literature regarding the impact of aging on innate immune cells, such as macrophages and neutrophils. This review seeks to address this gap, with emphasis on these cell types. Furthermore, although certain cancer immunotherapies, including immune checkpoint inhibitors (ICIs), have demonstrated efficacy across a broad spectrum of cancers, elderly patients are less likely to derive clinical benefit from these treatments. In some cases, they may even experience immune-related adverse events (irAEs). While senolytic strategies have shown promise in exerting anti-cancer effects, their adverse reactions and potential off-target effects present significant challenges. This review aims to elucidate the pro-cancer effects of immunosenescence, its implications for the efficacy and safety of ICIs, and potential anti-aging treatment strategies. In addition, optimizing anti-aging therapies to minimize adverse reactions and enhance therapeutic outcomes remains a critical focus for future research endeavors.

Medulloblastoma (MB) is the most common malignant brain tumor in children, with metastasis being the primary cause of recurrence and mortality. The tumor microenvironment (TME) plays a critical role in driving metastasis; however, the mechanisms underlying TME alterations in MB metastasis remain poorly understood.

To develop and validate machine learning (ML) models for predicting patient outcomes in MB and to investigate the role of TME components, particularly immune cells and immunoregulatory molecules, in metastasis.

ML models were constructed and validated to predict prognosis and metastasis in MB patients. Eight algorithms were evaluated, and the optimal model was selected. Lasso regression was employed for feature selection, and SHapley Additive exPlanations values were used to interpret the contribution of individual features to model predictions. Immune cell infiltration in tumor tissues was quantified using the microenvironment cell populations-counter method, and immunohistochemistry was applied to analyze the expression and distribution of specific proteins in tumor tissues.

The ML models identified metastasis as the strongest predictor of poor prognosis in MB patients, with significantly worse survival outcomes observed in metastatic cases. High infiltration of CD8+ T cells and cytotoxic T lymphocytes (CTLs), along with elevated expression of the TGFB1 gene encoding transforming growth factor beta 1 (TGF-β1), were strongly associated with metastasis. Independent transcriptomic and immunohistochemical analyses confirmed significantly higher CD8+ T cell/CTL infiltration and TGF-β1 expression in metastatic compared to nonmetastatic MB samples. Patients with both high CD8+ T cell/CTL infiltration and elevated TGFB1 expression in the context of metastasis exhibited significantly worse survival outcomes compared to patients with low expression and no metastasis.

This study identifies metastasis as the key prognostic factor in MB and reveals the pivotal roles of CD8+ T cells, CTLs, and TGF-β1 within the TME in promoting metastasis and poor outcomes. These findings provide a foundation for developing future therapeutic strategies targeting the TME to improve MB patient outcomes.

The Transforming Growth Factor-beta (TGF-β) signaling pathway, with SMAD4 as its central mediator, plays a pivotal role in regulating cellular functions, including growth, differentiation, apoptosis, and immune responses. While extensive research has elucidated SMAD4's role in tumorigenesis, its functions within immune cells remain underexplored. This review synthesizes current knowledge on SMAD4's diverse roles in various immune cells such as T cells, B cells, dendritic cells, and macrophages, highlighting its impact on immune homeostasis and pathogen response. Understanding SMAD4's role in immune cells is crucial, as its dysregulation can lead to autoimmune disorders, chronic inflammation, and immune deficiencies. The review emphasizes the significance of SMAD4 in immune regulation, proposing that deeper investigation could reveal novel therapeutic targets for immune-mediated conditions. Insights into SMAD4's involvement in processes like T cell differentiation, B cell class switch recombination, and macrophage polarization underscore its potential as a therapeutic target for a range of diseases, including autoimmune disorders and cancer.

Vaccine science, nanotechnology, and immunotherapy are at the forefront of cancer treatment strategies, each offering significant potential for enhancing tumor-specific immunity and establishing long-lasting immune memory to prevent tumor recurrence. Despite the promise of these personalized and precision-based anti-cancer approaches, challenges such as immunosuppression, suboptimal immune activation, and T-cell exhaustion continue to hinder their effectiveness. The limited clinical success of cancer vaccines often stems from difficulties in identifying effective antigens, efficiently targeting immune cells, lymphoid organs, and the tumor microenvironment, overcoming immune evasion, enhancing immunogenicity, and avoiding lysosomal degradation. However, numerous studies have demonstrated that integrating nanotechnology with immunotherapeutic strategies in vaccine development can overcome these challenges, leading to potent antitumor immune responses and significant progress in the field. This review highlights the critical components of cancer vaccine and nanovaccine strategies for immunomodulatory antitumor therapy. It covers general vaccine strategies, types of vaccines, antigen forms, nanovaccine platforms, challenges faced, potential solutions, and key findings from preclinical and clinical studies, along with future perspectives. To fully unlock the potential of cancer vaccines and nanovaccines, precise immunological monitoring during early-phase trials is essential. This approach will help identify and address obstacles, ultimately expanding the available options for patients who are resistant to conventional cancer immunotherapies.

Diabetic peripheral neuropathy (DPN) is a debilitating complication of diabetes mellitus, characterized by progressive nerve damage driven by chronic hyperglycemia and systemic inflammation. The pathophysiology of DPN is significantly influenced by pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α. These cytokines promote oxidative stress, vascular dysfunction, and neuronal degeneration by activating important signaling pathways including NF-κB and MAPK. While IL-6 promotes a pro-inflammatory microenvironment, increasing neuronal damage and neuropathic pain, TNF-α and IL-1β worsen Schwann cell failure by compromising axonal support and causing demyelination. Immune cell infiltration and TLR activation increase the inflammatory cascade in DPN, resulting in a persistent neuroinflammatory state that sustains peripheral nerve injury. The main characteristics of DPN are axonal degeneration, decreased neurotrophic support, and Schwann cell dysfunction, which weaken nerve transmission and increase susceptibility to damage. Advanced glycation end-products, TNF-α, and CXCL10 are examples of biomarkers that may be used for early diagnosis and disease progression monitoring. Additionally, crucial molecular targets have been found using proteomic and transcriptome techniques, enabling precision medicine for the treatment of DPN. This review emphasizes the importance of cytokine signaling in the pathogenesis of DPN and how cytokine-targeted treatments might reduce inflammation, restore nerve function, and improve clinical outcomes for diabetic patients.

Autoimmune diseases (ADs) result from an aberrant immune response, in which the body mistakenly targets its own tissues. The association between TGF-β1 gene polymorphisms and risk of developing autoimmune diseases remains to be established. This meta-analysis aimed to reassess the relationship between TGF-β1 T869C gene polymorphisms and susceptibility to autoimmune diseases.

We conducted a comprehensive search of seven electronic databases for case-control studies investigating the TGF-β1 T869C polymorphism in relation to autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjögren's syndrome, and juvenile idiopathic arthritis. The search encompassed publications published up to June 2024. Studies were categorized by ethnicity into three groups: Asian, Caucasian, and mixed-ethnicity groups. Five different genetic models were assessed, and the quality of the included studies was evaluated using the Newcastle-Ottawa Scale (NOS). Statistical analyses were performed using Stata 14.0, by calculating the odds ratio (OR) and 95% confidence interval (CI).

A total of 32 case-control studies (31 articles), comprising 4,304 cases and 4,664 controls, were included in this meta-analysis. The overall analysis indicated no significant association between TGF-β1 T869C gene polymorphism and susceptibility to autoimmune diseases. However, subgroup analyses based on race and disease status revealed significant associations. Ethnic subgroup analysis showed that the TGF-β1 T869C allele model (T vs C: OR = 1.422, 95% CI = 1.109-1.824, P = 0.006), homozygous model (TT vs CC: OR = 1.923, 95% CI = 1.232-3.004, P = 0.004), and dominant model (TT + TC vs CC: OR = 1.599, 95% CI = 1.164-2.196, P = 0.004) were associated with autoimmune disease susceptibility in Asians. In the disease subgroup analysis, the results showed that the TGF-β1 T869C allele model (T vs C: OR = 1.468, 95% CI = 1.210-1.781, P = 0.000), recessive model (TT vs TC + CC: OR = 1.418, 95% CI = 1.097-1.832, P = 0.008), dominant model (TT + TC vs CC: OR = 1.747, 95% CI = 1.330-2.295, P = 0.000), homozygous model (TT vs CC: OR = 1.937, 95% CI = 1.373-2.734, P = 0.000), and heterozygous model (TC vs CC: OR = 1.555, 95% CI = 1.199-2.016, P = 0.001) were associated with rheumatoid arthritis susceptibility.

The findings of this meta-analysis suggest that carrying the T allele of the TGF-β1 T869C polymorphism increases the risk of autoimmune diseases in Asian populations. Moreover, individuals carrying the T allele are at higher risk of developing rheumatoid arthritis.

Sepsis represents a serious disease burden that lacks effective treatment. Drug development for sepsis requires laboratory models that adequately represent sepsis patients. Simultaneous Transcriptome-based Activity Profiling of Signal Transduction Pathway (STAP-STP) technology quantitatively infers STP activity from mRNA levels of target genes of the STP-associated transcription factor. Here, we used STAP-STP technology to compare STP activities between sepsis patients and lipopolysaccharide (LPS)-based models. Activity scores of Androgen Receptor (AR), TGFβ, NFκB, JAK-STAT1/2, and JAK-STAT3 STPs were calculated based on publicly available transcriptome data. Peripheral blood mononuclear cells (PBMCs) from patients with Gram-negative sepsis, nor PBMCs stimulated with LPS in vitro, showed altered STP activity. Increased NFκB, JAK-STAT1/2, and JAK-STAT3 STP activity was found in whole blood stimulated with LPS in vitro, and in whole blood obtained after intravenous injection of LPS in humans in vivo; AR and TGFβ STP activity only increased in the in vivo LPS model. These results resembled previously reported STP activity in whole blood of sepsis patients. We provide the first comparison of STP activity between patients with sepsis and laboratory model systems. Results are of use for the refinement of sepsis model systems for rational drug development.

On the outermost edge of the body a dense network of dendritic cells (DCs), the so-called Langerhans cells (LCs), represents the first immune barrier. The establishment and maintenance of this epidermal network is dependent on the cytokine transforming growth factor-β1 (TGF-β1) expressed by keratinocytes (KC) and LCs. We recently identified a crucial downstream effector of TGF-β1, the receptor tyrosine kinase Axl. Axl belongs to the TAM receptor family, which also includes Tyro3 and Mer, and is activated through the vitamin K-dependent ligands Gas6 and Protein S.

We have now established that TGF-β1 dependent in vitro human LC generation from CD34+ progenitor cells can be enhanced by Axl over-expression.

Additionally, we supplemented vitamin K into serum-free human LC generation cultures in order to activate the endogenous ligands Gas6 and Protein S. Vitamin K exhibited supportive effects on LC differentiation and LC-associated gene expression. The vitamin K antagonist warfarin on the other hand, hindered efficient LC differentiation. Blocking antibodies against Axl abrogated the positive effect of vitamin K on LC differentiation. Lastly, vitamin K downregulated the immune activation marker CD86 during LC differentiation and blocked the upregulation of CD86 during LC activation in vitro, in an Axl independent manner.

Taken together, we provide evidence for the supportive role of vitamin K in regulating skin immunity.

Quercetin, a promising anti-inflammatory agent, faces challenges related to poor bioavailability and limited practical applications. β-glucan, a natural polysaccharide, can be specifically recognized by macrophages, making it an ideal targeting carrier to enhance therapeutic efficacy for macrophage-related dysfunctions. In this study, β-glucan conjugated quercetin nano-complexes (CM-Cur@QT) were developed to target macrophage and alleviate pro-inflammatory response in M1-like macrophages. The results demonstrated that CM-Cur@QT exhibited a spheric shape with an average diameter around 200 nm. FT-IR, 1H NMR, XRD and XPS analyses confirmed the complexation of CM-Cur@QT. This complex showed excellent stability during stimulated digestion, protecting QT from degradation while maintaining favorable antioxidant activity. After complexation, CM-Cur@QT displayed sustained uptake kinetics and enhanced accumulation in macrophages, with a 61.88 % increase compared to individual quercetin after 5 h of incubation. Meanwhile, CM-Cur@QT administration induced evidently cell cycle phases transitions and altered phagocytotic activity in M1-like macrophages. Furthermore, CM-Cur@QT reduced intracellular ROS accumulation, achieving a ROS scavenging rate of up to 49.92 %, compared to 25.59 % in quercetin group. This complex also effectively modulated TNF-a, IL-6 and TGF-β secretion profiles in pro-inflammatory macrophages, outperforming individual QT treatment. Notably, CM-Cur@QT facilitated anti-inflammatory effects while minimizing impacts on inactivated M0 macrophages. These findings underscore the potential of CM-Cur@QT as a promising agent for mitigating inflammatory disorders.

The coronavirus disease 2019 (COVID-19) has resulted in approximately 7.0 million fatalities between 2019 and 2022, underscoring a pressing need for comprehensive research into its underlying mechanisms and therapeutic avenues. A distinctive feature of severe COVID-19 is the dysregulated immune response characterized by excessive activation of immune cells and the consequent cytokine storms. Recent advancements in our understanding of cellular signaling pathways have illuminated the role of Transforming Growth Factor Beta (TGF-β) as a pivotal signaling molecule with significant implications for the pathogenesis of infectious diseases, including COVID-19. Emerging evidence reveals that TGF-β signaling, when activated by viral components or secondary pathways, adversely affects diverse cell types, particularly immune cells, and lung tissue, leading to complications such as pulmonary fibrosis. In our review article, we critically evaluate recent literature on the involvement of TGF-β signaling in the progression of COVID-19. We discuss a range of pharmacological interventions, including nintedanib, pirfenidone, corticosteroids, proton pump inhibitors, and histone deacetylase inhibitors, and their potential to modulate the TGF-β pathway in the context of COVID-19 treatment. Additionally, we explore ongoing clinical trials involving mesenchymal stem cells, low-dose radiation therapy, and artemisinin derivatives to assess their impact on TGF-β levels and subsequent clinical outcomes in COVID-19 patients. This review is particularly relevant at this juncture as the global health community continues to grapple with the ramifications of the COVID-19 pandemic, highlighting the urgent need for targeted therapeutic strategies aimed at TGF-β modulation to mitigate disease severity and improve patient outcomes.

Background: Abnormal elevation of transforming growth factor-beta (TGF-β) has been observed among Alzheimer's disease (AD) patients. This may be due to microglia-mediated release of proinflammatory cytokines, which promote neuroinflammation and neuronal apoptosis. Silencing of TGFBR1, a gene encoding TGF-β receptor type I (TGF-βR1), has resulted in neuronal survival from amyloid-beta (Aβ)-induced neurotoxicity. Therefore, the present study investigated the neuroprotective effect of TGF-βR1 inhibitors (RepSox, Galunisertib, and Vactosertib) against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. Methods: The neuroprotective effect of TGF-βR1 inhibitors against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation were investigated using the RealTime-Glo™ MT Cell Viability Assay. The inhibitory effect of TGF-βR1 inhibitors on Aβ-induced microglia-mediated production of proinflammatory cytokines (TNF-α and IL-1β) was determined using enzyme-linked immunosorbent assay (ELISA). Results: TGF-βR1 inhibitors (RepSox, Galunisertib, and Vactosertib) at the tested concentrations (6.25-150 nM) showed no significant cytotoxicity effects on SH-SY5Y and BV-2 cells. Moreover, treatments with these inhibitors exhibited neuroprotection on SH-SY5Y cells against Aβ-induced direct neurotoxicity. The trend of cell viability after 24 h treatment also supports the microscopic images of the cells' morphology. Furthermore, pretreatment with these inhibitors conferred indirect neuroprotective effect against Aβ-induced microglia-mediated neuroinflammation by attenuating the production of proinflammatory cytokines (TNF-α and IL-1β). Conclusion: The inhibition of the TGF-β signaling pathway in neuronal and microglia cells by TGF-βR1 inhibitors resulted in neuroprotection against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. Hence, targeting the TGF-β signaling pathway in both neuronal and microglia cells could provide a promising therapeutic strategy in AD.

Inborn errors of immunity (IEIs), also known as primary immunodeficiencies, are a group of genetic disorders affecting the development and function of the immune system. While IEIs traditionally present with recurrent infections, an increasing number of cases manifest with early-onset severe atopy, including atopic dermatitis, food allergies, asthma, and allergic rhinitis-features that are often overlooked. This can lead to delayed diagnosis and treatment, which is crucial for IEI patients due to the risk of severe infections. We conducted a literature search and reviewed all IEIs that can present with early-onset severe atopy. The hallmark features of these disorders often include early-onset, persistent, and severe atopic dermatitis, food allergies, and recurrent episodes of asthma, which may be refractory to treatments. Additionally, we discuss the importance of recognizing such severe atopy as a potential indicator of an underlying immune deficiency, particularly when accompanied by unusual infections, growth failure, or autoimmunity. This review aims to raise awareness of this association and emphasize the need for early diagnosis and genetic testing in patients with atypical or treatment-resistant allergic diseases, allowing for more timely diagnosis of underlying immunodeficiencies and appropriate treatments.

Astrocytes are the most abundant and morphologically complex glial cells that play active roles in the central nervous system (CNS). Recent research has identified shared and region-specific astrocytic genes and functions, elucidated the cellular origins of their regional diversity, and uncovered the molecular networks for astrocyte morphology, which are essential for their functional complexity. Reactive astrocytes exhibit a wide range of functional diversity in a context-specific manner in CNS disorders. This review discusses recent advances in understanding the molecular and morphological diversity of astrocytes in healthy individuals and those with neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis.

Prolonged immunosuppressive therapy in liver transplantation (LT) is associated with significant adverse effects, such as nephrotoxicity, metabolic complications, and heightened risk of infection or malignancy. Regulatory T cells (Tregs) represent a promising target for inducing immune tolerance in LT, with the potential to reduce or eliminate the need for life-long immunosuppression. This review summarizes current knowledge on the roles of Tregs in LT, highlighting their mechanisms and the impact of various immunosuppressive agents on Treg stability and function. The liver's distinct immunological microenvironment, characterized by tolerogenic antigen-presenting cells and high levels of interleukin (IL)-10 and transforming growth factor-β, positions this organ as an ideal setting for Treg-mediated tolerance. We discuss Treg dynamics in LT, their association with rejection risk, and their utility as biomarkers of transplant outcomes. Emerging strategies, including the use of low-dose calcineurin inhibitors with mammalian target of rapamycin inhibitors, adoptive Treg therapy, and low-dose IL-2, aim to enhance Treg function while providing sufficient immunosuppression. Thus, the future of LT involves precision medicine approaches that integrate Treg monitoring with tailored immunosuppressive protocols to optimize long-term outcomes for LT recipients.

Colony Stimulating Factor-1 Receptor (CSF-1R) signalling plays an important role in maturation, differentiation and activation of macrophages. Apposite generation and activation of macrophage phenotypes and subsequent adaptive immune response against any infection is decisive for a positive disease outcome. Antibiotic therapy is imperative for treating bacterial infections however antibiotics have off-target effects on host immune-cells. These effects could either be contextually beneficial or harmful and could potentially aid generation of infection persistence and antimicrobial resistance (AMR) via host immunosuppression. We had recently reported the immunosuppressive-mechanism of azithromycin-induced increased CSF-1R expression on murine-macrophages and bacterial-persistence in Balb/c model of intracellular infection. We further wanted to explore the molecular-mechanism behind these observations and tested GW2580-mediated CSF-1R blockade before azithromycin treatment during S. flexneri induced intracellular infection. In the presented study, we report that the azithromycin alters the protein expression or phosphorylation of transcription-factors ERK1/2, P38, AKT1, STAT3, STAT6, and EGR2 that are involved in macrophage polarisatoin and also take part in CSF-1R signalling pathways. Intrestingly, CSF-1R blockade using GW2580 abrogated or reversed the azithromycin-induced up- or down-regulated expression or phosphorylation of ERK1/2, P38, AKT1, STAT3, STAT6, and EGR2. We further validated our results in Balb/c model of S. flexneri infection. Intrestingly, the CSF-1R blocker and azithromycin treated mice showed batter recovery than the azithromycin alone treated mice and hence we report the aftermath of GW2580 with azithromycin treatment on disease and immunological outcome of an intracellular infection caused by Shigella flexneri.

The immune system relies on a delicate balance between attacking harmful pathogens and preserving the body's own tissues, a balance maintained by immune checkpoints. These checkpoints play a critical role in preventing autoimmune diseases by restraining excessive immune responses while allowing the immune system to recognize and destroy abnormal cells, such as tumors. In recent years, immune checkpoint inhibitors (ICIs) have become central to cancer therapy, enabling the immune system to target and eliminate cancer cells that evade detection. Traditional antibodies, such as IgGs, have been widely used in immune therapies but are limited by their size and complexity. Nanobodies (Nbs), derived from camelid heavy-chain-only antibodies, offer a promising alternative. These small, stable antibody fragments retain the antigen-binding specificity of traditional antibodies but have enhanced solubility and the ability to target otherwise inaccessible epitopes. This review explores the use of Nbs as ICIs, emphasizing their potential in cancer immunotherapy and other immune-related treatments. Their unique structural properties and small size make Nbs highly effective tools for modulating immune responses, representing a novel approach in the evolving landscape of checkpoint inhibitor therapies.

Male fertility results from a complex interplay of physiological, environmental, and genetic factors. It is conditioned by the properly developed anatomy of the reproductive system, hormonal regulation balance, and the interplay between different cell populations that sustain an appropriate and functional environment in the testes. Unfortunately, the mechanisms sustaining male fertility are not flawless and their perturbation can lead to infertility. Inflammation is one of the factors that contribute to male infertility. In the testes, it can be brought on by varicocele, obesity, gonadal infections, leukocytospermia, physical obstructions or traumas, and consumption of toxic substances. As a result of prolonged or untreated inflammation, the testicular resident cells that sustain spermatogenesis can suffer DNA damage, lipid and protein oxidation, and mitochondrial dysfunction consequently leading to loss of function in affected Sertoli cells (SCs) and Leydig cells (LCs), and the formation of morphologically abnormal dysfunctional sperm cells that lay in the basis of male infertility and subfertility. This is due mainly to the production and secretion of pro-inflammatory mediators, including cytokines, chemokines, and reactive oxygen species (ROS) by local immune cells (macrophages, lymphocytes T, mast cells) and tissue-specific cells [SCs, LCs, peritubular myoid cells (PMCs) and germ cells (GCs)]. Depending on the location, duration, and intensity of inflammation, these mediators can exert their toxic effect on different elements of the testes. In this review, we discuss the most prevalent inflammatory factors that negatively affect male fertility and describe the different ways inflammation can impair male reproductive function.

Chronic liver disease is characterised by persistent inflammation, tissue damage, and regeneration, which leads to steatosis, fibrosis, and, lastly, cirrhosis and hepatocellular carcinoma (HCC). HCC, the most prevalent form of primary liver cancer, is one of the leading causes of cancer-related mortality worldwide. The gut microbiota plays a fundamental role in human physiology, and disturbances in its critical balance are widely recognised as contributors to various pathological conditions, including chronic liver diseases, both infectious and non-infectious in nature. Growing interest in microbiota research has recently shifted the focus towards the study of intratumoural microbiota, referred to as the "oncobiome", which can significantly impact the development and progression of HCC. In this review, we discuss existing research and provide an overview of the microbiota influence on viral hepatitis, particularly in shaping the progression of liver disease caused by the hepatitis B and hepatitis C viruses. We also explore microbial dysbiosis and its contribution to the silent and dangerous progression of non-alcoholic fatty liver disease. Additionally, we address the impact of alcohol on the liver and its interaction with the microbiota, tracing the pathway from inflammation to cirrhosis and cancer. The review emphasises the most common etiologies of hepatocellular carcinoma.

The GDF15 protein, a member of the TGF-β superfamily, is a stress-induced multifunctional protein with many of its functions associated with the regulation of the immune system. GDF15 signaling provides a defence against the excessive inflammation induced by diverse stresses and tissue injuries. Given that the aging process is associated with a low-grade inflammatory state, called inflammaging, it is not surprising that the expression of GDF15 gradually increases with aging. In fact, the GDF15 protein is a core factor secreted by senescent cells, a state called senescence-associated secretory phenotype (SASP). Many age-related stresses, e.g., mitochondrial and endoplasmic reticulum stresses as well as inflammatory, metabolic, and oxidative stresses, induce the expression of GDF15. Although GDF15 signaling is an effective anti-inflammatory modulator, there is robust evidence that it is a pro-aging factor promoting the aging process. GDF15 signaling is not only an anti-inflammatory modulator but it is also a potent immunosuppressive enhancer in chronic inflammatory states. The GDF15 protein can stimulate immune responses either non-specifically via receptors of the TGF-β superfamily or specifically through the GFRAL/HPA/glucocorticoid pathway. GDF15 signaling stimulates the immunosuppressive network activating the functions of MDSCs, Tregs, and M2 macrophages and triggering inhibitory immune checkpoint signaling in senescent cells. Immunosuppressive responses not only suppress chronic inflammatory processes but they evoke many detrimental effects in aged tissues, such as cellular senescence, fibrosis, and tissue atrophy/sarcopenia. It seems that the survival functions of GDF15 go awry in persistent inflammation thus promoting the aging process and age-related diseases.

Neuroimmune communication in the body forms a bridge between two central regulatory systems of the body, i.e., nervous and immune systems. The cholinergic system is a crucial modulatory neurotransmitter in the central and peripheral nervous system. It includes the neurotransmitter acetylcholine (ACh), the enzyme required for the synthesis of ACh (choline acetyltransferase, ChAT), the enzyme required for its degradation (acetylcholinesterase, AChE), and cholinergic receptors (Nicotinic acetylcholine receptors and muscarinic acetylcholine receptors). The cholinergic system in neurons is well known for its role in cognitive function, sensory perception, motor control, learning, and memory processes. It has been shown that the non-neuronal cholinergic system (NNCS) is present in various tissues and immune cells and forms a neuroimmune communications system. In the present review, we discussed the NNCS on immune cells, its role in homeostasis and inflammatory reactions in the gut, and how it can be exploited in treating inflammatory responses.

A 45-day feeding study was carried out to assess the immune-stimulatory effects of capsicum oleoresin when added to rainbow trout diets. A total of 450 fish (mean weight: 155.20 ± 1.96 g) were distributed into 400 L tanks (30 fish/tank) across five experimental groups: control (CT, 0%), C7 (0.7%), C14 (1.4%), C21 (2.1%), and C28 (2.8%). Each group consisted of three replicate tanks. At the end of this period, hemato-biochemical parameters, innate immune responses, and immune-related gene expression levels were evaluated, and a histological examination of head kidney and liver sections was conducted. Finally, fish in all groups were challenged with Lactococcus garvieae and observed for an additional 20 days. The results revealed that oleoresin supplementation enhanced the immune responses of the treated fish, which was evidenced by the increased globulin, total protein, respiratory burst activity, and total immunoglobulin levels. The highest expression levels of the il-8, il-1β, TGF-β, and SAA genes was noticed in the C7 group, as compared with the results for the other groups. The IgT gene expression levels were higher in all experimental groups than in the CT group, and this increase was at the highest level in the C28 group. Following the bacterial challenge, all experimental groups displayed higher survival rates compared to that of the CT group. These values were 75.93, 72.22, 46.30, 33.33, and 29.63% in the C7, C14, C21, C28, and CT groups, respectively, with the C7 group displaying the highest survival rate among the groups. The histological examination of liver and head kidney tissues revealed that higher doses (in the C21 and C28 groups) showed an increase in cytoplasmic vacuolization, which causes adverse effects on fish health. However, the C7 group displayed normal histological structure in both tissues. Taken together, the most favorable immune responses were achieved in the C7 group, suggesting that 0.7% oleoresin could be applied to rainbow trout to boost immunity and protect the fish from diseases.

The evolutionary conserved transforming growth factor beta (TGF-β) signaling pathway participates in the regulation of several cellular functions and tissue homeostasis. In the model Drosophila melanogaster , the two TGF-β signaling pathway branches Bone Morphogenic Protein (BMP) and Activin are involved in important developmental and immune processes. Here we examine the effect of mutations in various BMP and Activin signaling molecules on the fly lifespan. We find that loss-of-function fly mutants for distinct Activin and BMP components differentially modulate the fly lifespan. These results indicate that the TGF-β signaling pathways act as regulators of lifespan in the adult D. melanogaster .

Interleukin-37 (IL-37) has anti-inflammatory properties in innate and adaptive immunity. Patients with multiple sclerosis (MS), an autoimmune inflammatory demyelinating disease of the central nervous system (CNS), have increased serum levels of IL-37. However, it is unknown whether IL-37 has an inhibitory effect on ongoing autoimmune neuroinflammation, thus offering a potential MS therapy.

Here, we examined the effect of IL-37 in an experimental autoimmune encephalomyelitis (EAE) model after disease onset to determine if it was protective.

IL-37-treated mice developed a less severe disease than control mice, with reduced demyelination as determined by increased expression of myelin basic protein. IL-37 suppressed inflammation by decreasing infiltration of CD4 + T cells into the CNS and increasing the frequency of regulatory T cells, while IL-10 expression by CD4 + T cells decreased over time in the CNS.

Our findings confirm the immunomodulatory role of IL-37 in CNS inflammation during ongoing disease, thus indicating the potential of IL-37 as an inhibitory reagent for MS therapy.