Impact of TNF and IL-33 Cytokines on Mast Cells in Neuroinflammation.

Mast cells (MCs) are derived from hematopoietic progenitors, mature in vascularized tissues, and participate in innate and acquired immunity. Neuroinflammation is a highly debated topic in the biomedical literature; however, the impact of tumor necrosis factor (TNF) and IL-33 on MCs in the brain has not been widely addressed. MCs can be activated by IgE binding to FcεRI, as well as by different antigens. After activation, MCs mediate various immunological and inflammatory responses through TNF and IL-33. TNF has two receptors: TNFR1, a p55 molecule, and TNFR2, a p75 molecule. This cytokine is the only one of its kind to be stored in the granules of MCs and can also be generated by de novo synthesis via mRNA. In the central nervous system (CNS), TNF is produced almost exclusively by microglial cells, neurons, astrocytes, and, minimally, by endothelial cells. After its release into brain tissue, TNF rapidly induces the adhesion molecules endothelial leukocyte adhesion molecule 1 (ELAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) in endothelial cells. TNF causes the chemoattraction of neutrophils by inducing several molecules, including CXC chemokines (IL-8). Both MCs and microglial cells act as a primary barrier against foreign molecules in the CNS, producing pro-inflammatory cytokines such as IL-33. IL-33 belongs to the IL-1 family, is activated through the ST2L/IL1-RAcP receptor complex, and mediates both the innate and adaptive immune response. IL-33 is a nuclear transcription factor expressed in the brain, where it induces pro-inflammatory cytokines (TNF and IL-1) and chemokines (CCL2, CCL3, CCL5, and CXCL10). Therefore, MCs and microglia in the CNS are a source of pro-inflammatory cytokines, including TNF and IL-33, that mediate many brain diseases. The inhibition of TNF and IL-33 may represent a new therapeutic approach that could complement existing neuroinflammatory therapies.

Effects of intra-articular injection of platelet-rich plasma on the inflammatory process and histopathological characteristics of cartilage and synovium in animals with osteoarthritis: a systematic review with meta-analysis.

BACKGROUND: Osteoarthritis (OA) affects the entire joint, causing structural changes in articular cartilage, subchondral bone, ligaments, capsule, synovial membrane, and periarticular muscles that afflicts millions of people globally, leading to persistent pain and diminished quality of life. The intra-articular use of platelet-rich plasma (PRP) is gaining recognition as a secure therapeutic approach due to its potential regenerative capabilities. However, there is controversial clinical data regarding efficacy of PRP for OA treatment. In this context, gathering scientific evidence on the effects of PRP in treating OA in animal models could provide valuable insights into understanding its impact on aspects like cartilage health, synovial tissue integrity, and the inflammatory process in affected joints. Thus, the objective of this study was to assess the effects of PRP injections on inflammation and histopathological aspects of cartilage and synovium in animal models of OA through a comprehensive systematic review with meta-analysis. METHODS: A electronic search was conducted on Medline, Embase, Web of Science, The Cochrane Library, LILACS, and SciELO databases for relevant articles published until June 2022. A random-effects meta-analysis was employed to synthesize evidence on the histological characteristics of cartilage and synovium, as well as the inflammatory process. The GRADE approach was utilized to categorize the quality of evidence, and methodological quality was assessed using SYRCLE's RoB tool. RESULTS: Twenty-one studies were included in the review, with twelve of them incorporated into the meta-analysis. PRP treatment demonstrated superior outcomes compared to the control group in terms of cartilage histology (very low quality; p = 0.0002), synovium histology (very low quality; p < 0.0001), and reductions in proinflammatory markers, including IL-1 (low quality; p = 0.002), IL-6 (very low quality; p < 0.00001), and TNF-α (very low; p < 0.00001). However, PRP treatment did not yield a significant impact on PDGF-A levels (very low quality; p = 0.81). CONCLUSION: PRP appears capable of reducing proinflammatory markers (IL-1, IL-6, TNF-α) and mitigating cartilage and synovium damage in animals with OA. However, the levels of evidence of these findings are low to very low. Therefore, more rigorous studies with larger samples are needed to improve the quality of evidence. PROSPERO REGISTRATION: CRD42022250314.

Effects of antioxidant vitamins (A, D, E) and trace elements (Cu, Mn, Se, Zn) administration on gene expression, metabolic, antioxidants and immunological profiles during transition period in dromedary camels.

BACKGROUND: Nutrition has a primary role for optimum expression of genetic potential, and most of the farmers have limited resources of green fodder. Hence, a fat-soluble vitamin, especially vitamin A and E and trace elements remained most critical in the animal's ration and affects their productive and reproductive performance adversely. Animals cannot be able to produce these vitamins in their bodies; hence, an exogenous regular supply is needed to fulfil the physiological needs and to maintain high production performance. This study elucidated effects of antioxidant vitamins (A, D, E) and trace elements (Cu, Mn, Se, Zn) administration on gene expression, metabolic, antioxidants and immunological parameters in dromedary camels during transition period. RESULTS: At 0 day, there were no appreciable differences in the expression patterns of the metabolic (IGF-I, ACACA, SCD, FASN, LPL, and BTN1A1) genes between the control and treatment groups, despite lower levels. A substantial variation in the mRNA levels of SOD1, SOD3, PRDX2, PRDX3, PRDX4, PRDX6, and AhpC/TSA was observed between the control and treatment groups, according to the antioxidant markers. In comparison to the control group, the treatment group displayed a significant up-regulation at 0 and 21 days. The treatment and control groups exhibited substantial differences in the mRNA values of IL-1α, IL-1ß, IL-6, and TNFα, as indicated by immunological markers. In comparison to the control group, there was a noticeable down-regulation in the treatment group at 0 and + 21 days. But IL10 produced the opposite pattern. No significant difference was observed in glucose, cholesterol, triglyceride, HDL, total protein, NEFA, BHBA, cortisol and IGF-1 levels between control and treatment group. The activity of serum GPx, SOD and TAC was significantly affected by time and treatment x time in supplemented groups as compared with control group. IL-1, IL-1, IL-6, and TNF were noticeably greater in the control group and lower in the treatment group. Additionally, in all groups, the concentration of all pro-inflammatory cytokines peaked on the day of delivery and its lowest levels showed on day 21 following calving. The IL-10 level was at its peak 21 days prior to calving and was lowest on calving day. CONCLUSION: The results demonstrated a beneficial effect of antioxidant vitamins and trace elements on the metabolic, antioxidant and immunological markers in dromedary camels throughout their transition period.

Efficacy of colchicine in addition to anakinra in patients with recurrent pericarditis.

AIM: Anakinra, an anti IL-1 agent targeting IL-1 alfa and beta, is available for the treatment of recurrent pericarditis in cases with corticosteroid dependence and colchicine resistance after failure of conventional therapies. However, it is unclear if the combination with colchicine, a non-specific inhibitor of the inflammasome targeting the same inflammatory pathway of IL-1, could provide additional benefit to prevent further recurrences. The aim of the present observational study is to assess whether the addition of colchicine on top of anakinra could prolong the time to first recurrence and prevent recurrences better than anakinra alone. METHODS: International, all-comers, multicentre, retrospective observational cohort study analysing all consecutive patients treated with anakinra for corticosteroid-dependent and colchicine-resistant recurrent pericarditis. The efficacy endpoint was recurrence rate and the time to the first recurrence. RESULTS: A total of 256 patients (mean age 45.0±15.4 years, 65.6% females, 80.9% with idiopathic/viral aetiology) were included. 64 (25.0%) were treated with anakinra as monotherapy while 192 (75.0%) with both anakinra and colchicine. After a follow-up of 12 months, 56 (21.9%) patients had recurrences. Patients treated with colchicine added to anakinra had a lower incidence of recurrences (respectively, 18.8% vs 31.3%; p=0.036) and a longer event-free survival (p=0.025). In multivariable analysis, colchicine use prevented recurrences (HR 0.52, 95% CI 0.29 to 0.91; p=0.021). CONCLUSIONS: The addition of colchicine on top of anakinra treatment could be helpful to reduce recurrences and prolong the recurrence-free survival.

Human neutrophils drive skin autoinflammation by releasing interleukin (IL)-26.

Autoinflammation is a sterile inflammatory process resulting from increased neutrophil infiltration and overexpression of IL-1 cytokines. The factors that trigger these events are, however, poorly understood. By investigating pustular forms of psoriasis, we show that human neutrophils constitutively express IL-26 and abundantly release it from granular stores upon activation. In pustular psoriasis, neutrophil-derived IL-26 drives the pathogenic autoinflammation process by inducing the expression of IL-1 cytokines and chemokines that further recruit neutrophils. This occurs via activation of IL-26R in keratinocytes and via the formation of complexes between IL-26 and microbiota DNA, which trigger TLR9 activation of neutrophils. Thus our findings identify neutrophils as an important source of IL-26 and point to IL-26 as the key link between neutrophils and a self-sustaining autoinflammation loop in pustular psoriasis.

Adult-Onset Still's Disease (AOSD): Advances in Understanding Pathophysiology, Genetics and Emerging Treatment Options.

Adult-onset Still's disease (AOSD) is a multisystemic complex disorder clinically characterised by episodes of spiking fever, evanescent rash, polyarthritis or diffuse arthralgias; multiorgan involvement may develop according to the hyper-inflammatory extent. The pathogenesis of AOSD is not completely recognised. The central role of macrophage activation, which results in T helper 1 (Th1) cell cytokine activation, is well established. Pro-inflammatory cytokines such as interleukin (IL)-1, IL-6 and IL-18 play a fundamental role in disease onset and progression. The disease may develop in both children and adults with overlapping clinical features, and although several subsets depending on the clinical manifestations and the cytokines expressed have been identified, the dichotomy between systemic juvenile idiopathic arthritis (sJIA) and AOSD nowadays has been overcome, and the pathology is considered a disease continuum between ages. Various therapeutic approaches have been evaluated thus far, and different compounds are under assessment for AOSD treatment. Historically, glucocorticoids have been employed for treating systemic manifestations of Still's disease, while conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) demonstrated efficacy in controlling the articular manifestations. Currently, biological (b) DMARDs are widely employed; IL-1 inhibitors such as anakinra and canakinumab have proven to have high efficacy and an excellent safety profile and the anti-IL-6 tocilizumab is approved for sJIA, with several trials and longitudinal studies confirming its efficacy and safety. Moreover, in the light of the 'window of opportunity', new evidence showed that the earlier these treatments are initiated, the sooner clinical inactivity can be achieved. Other treatment options are being considered since several molecules involved in the disease pathophysiology can be targeted through various mechanisms. This review will provide a broad overview of AOSD pathophysiology, insights into specific organ manifestations and the currently available treatments with the identification of potential therapeutic targets involved in AOSD pathogenesis will be outlined.

Role of Interleukin 1 Receptor 2 in Kidney Disease.

The interleukin 1 (IL-1) family plays a significant role in the innate immune response. IL-1 receptor 2 (IL-1R2) is the decoy receptor of IL-1. It is a negative regulator that can be subdivided into membrane-bound and soluble types. IL-1R2 plays a role in the IL-1 family mainly through the following mechanisms: formation of inactive signaling complexes upon binding to the receptor auxiliary protein and inhibition of ligand IL-1 maturation. This review covers the roles of IL-1R2 in kidney disorders. Chronic kidney disease, acute kidney injury, lupus nephritis, IgA nephropathy, renal clear cell carcinoma, rhabdoid tumor of kidney, kidney transplantation, and kidney infection were all shown to have abnormal IL-1R2 expression. IL-1R2 may be a potential marker and a promising therapeutic target for kidney disease.

Assessing the impact of dental restorative materials on fibroblast cells: an immunohistochemical and ELISA analysis.

In this study, our aim was to investigate the effects of restorative materials such as composite, compomer and high viscosity glass ionomer, which are frequently used in dentistry, on L929 fibroblast cells by evaluating the oxidative stress parameters, pro- and anti-inflammatory cytokines, and apoptosis markers. L929 fibroblast cells were cultured, and dental filling materials were applied in two doses (50 and 100 µl). Immunohistochemical staining was performed for experimental groups with Anti-Bax and Anti-Caspase 9 antibodies. Then, ELISA technique was used to detect the level of TNF-alpha, TGF-beta, IL-1-beta, IL-6, IL-10, LPO and CAT. In the light of the data, the examined dental filling materials were effective on increasing the TGF-beta, IL-10, LPO and CAT levels, and decreasing the TNF-alpha, IL-1-beta, and IL-6 levels. The histological micrographs were also support the issues. When the levels of H-score in Caspase 9 labeled micrographs were evaluated, the mean of the control group was lower than the mean of the experimental groups. Biocompatibility varies according to the content of the material, the amount of residual monomer, and its solubility. Although all the experimental groups have cytotoxic effects, the least effect is seen in the Omnichroma group.

Loss of interleukin 1 signaling causes impairment of microglia- mediated synapse elimination and autistic-like behaviour in mice.

In the last years, the hypothesis that elevated levels of proinflammatory cytokines contribute to the pathogenesis of neurodevelopmental diseases has gained popularity. IL-1 is one of the main cytokines found to be elevated in Autism spectrum disorder (ASD), a complex neurodevelopmental condition characterized by defects in social communication and cognitive impairments. In this study, we demonstrate that mice lacking IL-1 signaling display autistic-like defects associated with an excessive number of synapses. We also show that microglia lacking IL-1 signaling at early neurodevelopmental stages are unable to properly perform the process of synapse engulfment and display excessive activation of mammalian target of rapamycin (mTOR) signaling. Notably, even the acute inhibition of IL-1R1 by IL-1Ra is sufficient to enhance mTOR signaling and reduce synaptosome phagocytosis in WT microglia. Finally, we demonstrate that rapamycin treatment rescues the defects in IL-1R deficient mice. These data unveil an exclusive role of microglial IL-1 in synapse refinement via mTOR signaling and indicate a novel mechanism possibly involved in neurodevelopmental disorders associated with defects in the IL-1 pathway.

The multi-protective effect of IL-37-Smad3 against ox-LDL induced dysfunction of endothelial cells.

Atherosclerosis is a lipid-driven inflammatory arterial disease, with one crucial factor is oxidized low-density lipoprotein (ox-LDL), which can induce endothelial dysfunction through endoplasmic reticulum stress (ERS). Interleukin-37 (IL-37) exerts vascular protective functions. This study aims to investigates whether IL-37 can alleviate ERS and autophagy induced by ox-LDL, therely potentialy treating atherosclerosis. We found that ox-LDL enhances the wound healing rate in Rat Coronary Artery Endothelial Cells (RCAECs) and IL-37 reduce the ox-LDL-induced pro-osteogenic response, ERS, and autophagy by binding to Smad3. In RCAECs treated with ox-LDL and recombinant human IL-37, the wound healing rate was mitigated. The expression of osteogenic transcription factors and proteins involved in the ERS pathway was reduced in the group pretreated with IL-37 and ox-LDL. However, these responses were not alleviated when Smads silenced. Electron microscopy revealed that the IL-37/Smad3 complex could suppress endoplasmic reticulum autophagy under ox-LDL stimulation. Thus, IL-37 might treat atherosclerosis through its multi-protective effect by binding Smad3.

Loss of T follicular regulatory cell-derived IL-1R2 augments germinal center reactions via increased IL-1.

Inappropriate immune activity is key in the pathogenesis of multiple diseases, and it is typically driven by excess inflammation and/or autoimmunity. IL-1 is often the effector owing to its powerful role in both innate and adaptive immunity, and, thus, it is tightly controlled at multiple levels. IL-1R2 antagonizes IL-1, but effects of losing this regulation are unknown. We found that IL-1R2 resolves inflammation by rapidly scavenging free IL-1. Specific IL-1R2 loss in germinal center (GC) T follicular regulatory (Tfr) cells increased the GC response after a first, but not booster, immunization, with an increase in T follicular helper (Tfh) cells, GC B cells, and antigen-specific antibodies, which was reversed upon IL-1 blockade. However, IL-1 signaling is not obligate for GC reactions, as WT and Il1r1-/- mice showed equivalent phenotypes, suggesting that GC IL-1 is normally restrained by IL-1R2. Fascinatingly, germline Il1r2-/- mice did not show this phenotype, but conditional Il1r2 deletion in adulthood recapitulated it, implying that compensation during development counteracts IL-1R2 loss. Finally, patients with ulcerative colitis or Crohn's disease had lower serum IL-1R2. All together, we show that IL-1R2 controls important aspects of innate and adaptive immunity and that IL-1R2 level may contribute to human disease propensity and/or progression.

IL-1α is required for T cell-driven weight loss after respiratory viral infection.

Respiratory viral infections remain a major cause of hospitalization and death worldwide. Patients with respiratory infections often lose weight. While acute weight loss is speculated to be a tolerance mechanism to limit pathogen growth, severe weight loss following infection can cause quality of life deterioration. Despite the clinical relevance of respiratory infection-induced weight loss, its mechanism is not yet completely understood. We utilized a model of CD 8+ T cell-driven weight loss during respiratory syncytial virus (RSV) infection to dissect the immune regulation of post-infection weight loss. Supporting previous data, bulk RNA sequencing indicated significant enrichment of the interleukin (IL)-1 signaling pathway after RSV infection. Despite increased viral load, infection-associated weight loss was significantly reduced after IL-1α (but not IL-1ß) blockade. IL-1α depletion resulted in a reversal of the gut microbiota changes observed following RSV infection. Direct nasal instillation of IL-1α also caused weight loss. Of note, we detected IL-1α in the brain after either infection or nasal delivery. This was associated with changes in genes controlling appetite after RSV infection and corresponding changes in signaling molecules such as leptin and growth/differentiation factor 15. Together, these findings indicate a lung-brain-gut signaling axis for IL-1α in regulating weight loss after RSV infection.

IL-36 antagonism blunts the proliferation and migration of oral squamous cell carcinoma cells.

IL-36 is known to mediate inflammation and fibrosis. Nevertheless, IL-36 signalling axis has also been implicated in cancer, although understanding of exact contribution of IL-36 to cancer progression is very limited, partly due to existence of multiple IL-36 ligands with agonistic and antagonistic function. Here we explored the role of IL-36 in oral squamous cell carcinoma (OSCC). Firstly, we analyzed expression of IL-36 ligands and receptor and found that the expression of IL-36γ was significantly higher in head and neck cancer (HNSCC) than that of normal tissues, and that the high expression of IL-36γ predicted poor clinical outcomes. Secondly, we investigated the direct effect of IL-36γ on OSCC cells and found that IL-36γ stimulated proliferation of OSCC cells with high expression of IL-36R expression. Interestingly, IL-36γ also promoted migration of OSCC cells with low to high IL-36R expression. Critically, both proliferation and migration of OSCC cells induced by IL-36γ were abrogated by anti-IL-36R mAb. Fittingly, RNA sequence analysis revealed that IL-36γ regulated genes involved in cell cycle and cell division. In summary, our results showed that IL-36γ can be a tumor-promoting factor, and targeting of IL-36R signalling may be a beneficial targeted therapy for patients with abnormal IL-36 signalling.

"How to Release or Not Release, That Is the Question." A Review of Interleukin-1 Cellular Release Mechanisms in Vascular Inflammation.

Cardiovascular disease remains the leading cause of death worldwide, characterized by atherosclerotic activity within large and medium-sized arteries. Inflammation has been shown to be a primary driver of atherosclerotic plaque formation, with interleukin-1 (IL-1) having a principal role. This review focuses on the current state of knowledge of molecular mechanisms of IL-1 release from cells in atherosclerotic plaques. A more in-depth understanding of the process of IL-1's release into the vascular environment is necessary for the treatment of inflammatory disease processes, as the current selection of medicines being used primarily target IL-1 after it has been released. IL-1 is secreted by several heterogenous mechanisms, some of which are cell type-specific and could provide further specialized targets for therapeutic intervention. A major unmet challenge is to understand the mechanism before and leading to IL-1 release, especially by cells in atherosclerotic plaques, including endothelial cells, vascular smooth muscle cells, and macrophages. Data so far indicate a heterogeneity of IL-1 release mechanisms that vary according to cell type and are stimulus-dependent. Unraveling this complexity may reveal new targets to block excess vascular inflammation.

Long-term music stimulating alleviated the inflammatory responses caused by acute noise stress on the immune organs of broilers by NF-κB signaling pathway.

As an environmental enrichment, music can positively influence the immune function, while noise has an adverse effect on the physical and mental health of humans and animals. However, whether music-enriched environments mitigate noise-induced acute stress remains unclear. To investigate the anti-inflammatory effects of music on the immune organs of broiler chickens under conditions of early-life acute noise stress, 140 one-day-old white feather broilers (AA) were randomly divided into four groups: control (C), the music stimulation (M) group, the acute noise stimulation (N) group, the acute noise stimulation followed by music (NM) group. At 14 days of age, the N and NM groups received 120 dB noise stimulation for 10 min for one week. After acute noise stimulation, the NM group and M group were subjected to continuous music stimulation for 14 days (6 h per day, 60 dB). At 28 days of age, the body temperature of the chicks, the histopathological changes, quantification of ROS-positive density and apoptosis positivity in tissues of spleen, thymus, and bursa of Fabricius (BF) were measured. The results showed that acute noise stimulation led to an increase in the number and area of splenic microsomes and the cortex/medulla ratio of the detected immune organs. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) of immune tissues of broilers in N group were decreased compared to the broilers in C group, while the mRNA levels of malondialdehyde (MDA), TNF-α, IL-1, and IL-1ß increased. In addition, the gene and protein expression levels of IKK, NF-κB, and IFN-γ of three immune organs from broilers in the N group were increased. Compared to the C and N group, chickens from the NM group showed a decrease in the number and area of splenic follicles, an increase in the activities of SOD and GSH-Px, and a decrease in the expression levels of MDA, TNF-α, IL-1, and IL-1ß. Therefore, a music-enriched environment can attenuate oxidative stress induced by acute noise stimulation, inhibiting the activation of the NF-κB signaling pathway and consequently alleviating the inflammatory response in immune organs.

Restraint stress-induced effects on learning, memory, cognition, and expression of transcripts in different brain regions of mice.

BACKGROUND: Stress is one of the prevalent factors influencing cognition. Several studies examined the effect of mild or chronic stress on cognition. However, most of these studies are limited to a few behavioral tests or the expression of selected RNA/proteins markers in a selected brain region. METHODS: This study examined the effect of restraint stress on learning, memory, cognition, and expression of transcripts in key learning centers. Male mice were divided into three groups (n = 6/group)-control group, stress group (adult stressed group; S), and F1 group (parental stressed group). Stress group mice were subjected to physical restraint stress for 2 h before light offset for 2 weeks. The F1 group comprised adult male mice born of stressed parents. All animals were subjected to different tests and were sacrificed at the end. Transcription levels of Brain-Derived Neurotrophic Factor (Bdnf), Tyrosine kinase (TrkB), Growth Associated Protein 43 (Gap-43), Neurogranin (Ng), cAMP Response Element-Binding Protein (Creb), Glycogen synthase kinase-3ß (Gsk3ß), Interleukine-1 (IL-1) and Tumour necrosis factor-α (Tnf-α) were studied. RESULTS: Results show that both adult and parental stress negatively affect learning, memory and cognition, as reflected by taking longer time to achieve the task or showing reduced exploratory behavior. Expression of Bdnf, TrkB, Gsk3ß and Ng was downregulated, while IL-1 and Tnf-α were upregulated in the brain's cortex, thalamus, and hippocampus region of stressed mice. These effects seem to be relatively less severe in the offspring of stressed parents. CONCLUSIONS: The findings suggest that physical restraint stress can alter learning, memory, cognition, and expression of transcripts in key learning centers of brain.

Exploring the multifaceted effects of Interleukin-1 in lung cancer: From tumor development to immune modulation.

Lung cancer, acknowledged as one of the most fatal cancers globally, faces limited treatment options on an international scale. The success of clinical treatment is impeded by challenges such as late diagnosis, restricted treatment alternatives, relapse, and the emergence of drug resistance. This predicament has led to a saturation point in lung cancer treatment, prompting a rapid shift in focus towards the tumor microenvironment (TME) as a pivotal area in cancer research. Within the TME, Interleukin-1 (IL-1) is abundantly present, originating from immune cells, tissue stromal cells, and tumor cells. IL-1's induction of pro-inflammatory mediators and chemokines establishes an inflammatory milieu influencing tumor occurrence, development, and the interaction between tumors and the host immune system. Notably, IL-1 expression in the TME exhibits characteristics such as staging, tissue specificity, and functional pluripotency. This comprehensive review aims to delve into the impact of IL-1 on lung cancer, encompassing aspects of occurrence, invasion, metastasis, immunosuppression, and immune surveillance. The ultimate goal is to propose a novel treatment approach, considering the intricate dynamics of IL-1 within the TME.