Interleukin-1 Receptor Research Articles

Simple dysmood disorder, a mild subtype of major depression, is not an inflammatory condition: Depletion of the compensatory immunoregulatory system.

A recent study conducted by the laboratory of the first author revealed that major depression is composed of two distinct subtypes: major dysmood disorder (MDMD) and simple dysmood disorder (SDMD). The latter is a less severe phenotype with fewer aberrant biological pathways. MDMD, but not SDMD, patients were identified to have highly sensitized cytokine/growth factor networks using stimulated whole blood cultures. However, no information regarding serum cytokines/chemokines/growth factors in SDMD is available. This case-control study compares 48 serum cytokines/chemokines/growth factors in academic students with SDMD (n=64) and first episode (FE)-SDMD (n=47) to those of control students (n=44) using a multiplex assay. Both FE-SDMD and SDMD exhibited a notable inhibition of immune profiles, such as the compensatory immunoregulatory response system (CIRS) and alternative M2 macrophage and T helper-2 (Th-2) profiles. We observed a substantial reduction in the serum concentrations of five proteins: interleukin (IL)-4, IL-10, soluble IL-2 receptor (sIL-2R), IL-12p40, and macrophage colony-stimulating factor. A considerable proportion of the variability observed in suicidal behaviors (26.7%) can be accounted for by serum IL-4, IL-10, and sIL-2R (all decreased), CCL11 (eotaxin) and granulocyte CSF (both increased). The same biomarkers (except for IL-10), accounted for 25.5% of the variance in SDMS severity. A significant correlation exists between decreased levels of IL-4 and elevated ratings of the brooding type of rumination. SDMD is characterized by the suppression of the CIRS profile, which signifies a disruption of immune homeostasis and tolerance, rather than the presence of an inflammatory response.

Pretransplant targeting of TNFRSF25 and CD25 stimulates recipient Tregs in target tissues ameliorating GVHD post-HSCT.

The current approach to minimize transplant-associated complications, including graft-versus-host disease (GVHD) includes long-term pharmacological immune suppression frequently accompanied by unwanted side effects. Advances in targeted immunotherapies regulating alloantigen responses in the recipient continue to reduce the need for pan-immunosuppression. Here, in vivo targeting of the TNF superfamily receptor 25 (TNFRSF25) and the high affinity IL-2 receptor with a TL1A-Ig fusion protein and low dose IL-2, respectively, was used to pretreat recipient mice prior to allogeneic-HSCT (aHSCT). Pretreatment induced Treg expansion persisting early post-aHSCT leading to diminished GVHD and improved transplant outcomes. Expansion was accompanied by an increase in frequency of stable and functionally active Tregs as evidenced by in vitro assays using cells from major GVHD target tissues including colon, liver, and eye. Importantly, pretreatment supported epithelial cell function/integrity, a diverse microbiome including reduction of pathologic bacteria overgrowth and promotion of butyrate producing bacteria, while maintaining physiologic levels of obligate/facultative anaerobes. Notably, using a sphingosine 1-phosphate receptor agonist to sequester T cells in lymphoid tissues, we found that the increased tissue Treg frequency included resident CD69 + CD103 + FoxP3 + hepatic Tregs. In contrast to infusion of donor Treg cells, the strategy developed here resulted in the presence of immunosuppressive target tissue environments in the recipient prior to the receipt of donor allo-reactive T cells and successful perseveration of GVL responses. We posit strategies that circumvent the need of producing large numbers of ex-vivo manipulated Tregs, may be accomplished through in vivo recipient Treg expansion, providing translational approaches to improve aHSCT outcomes.

Elucidating the Causal Dynamics between Inflammatory Proteins and Atrial Fibrillation Risk Through Bidirectional Mendelian Randomization.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with significant morbidity and mortality. Inflammation has been implicated in the pathogenesis of AF, but the causal relationship between specific inflammatory proteins and AF risk is not well established. This study aims to clarify this relationship using a bidirectional two-sample Mendelian Randomization (TSMR) approach. Employing a bidirectional Mendelian Randomization (MR) method, we analyzed genetic variants as instrumental variables (IVs) to investigate the influence of 91 circulating inflammatory proteins on AF risk. This approach allowed us to assess the potential causal effects of inflammatory proteins on AF and vice versa, thus providing a comprehensive understanding of the bidirectional nature of their relationship. Seven inflammatory proteins were significantly associated with AF risk. Three proteins increased the risk: Fibroblast Growth Factor 5 (FGF-5) with an odds ratio (OR) of 1.0743 (95% CI: 1.0466-1.1027, p=7.41E-08), Tumor Necrosis Factor (TNF) with an OR of 1.0832 (95% CI: 1.0261-1.1434, p=0.0038), and Interleukin-2 Receptor Subunit Beta (IL-2RB) with an OR of 1.0814 (95% CI: 1.0151-1.1519, p=0.0153). Four proteins showed a protective effect: CD40 Ligand Receptor (CD40) with an OR of 0.9671 (95% CI: 0.9392-0.9959, p=0.0254), Fms-related Tyrosine Kinase 3 Ligand (FIt3L) with an OR of 0.9553 (95% CI: 0.9173-0.9949, p=0.0274), Leukemia Inhibitory Factor Receptor (LIF-R) with an OR of 0.9254 (95% CI: 0.8678- 0.9868, p=0.0181), and Sulfotransferase 1A1 (ST1A1) with an OR of 0.9461 (95% CI: 0.9097-0.9839, p=0.0056). The reverse MR analysis revealed no significant effects of AF on the levels of these inflammatory proteins, suggesting a unidirectional causality from proteins to AF. This bidirectional MR study provides robust evidence for a causal relationship between specific inflammatory proteins and AF risk. The identified proteins could serve as potential biomarkers for AF risk stratification and targets for therapeutic intervention, offering new insights into the pathophysiology of AF and avenues for future research.

IL-6 Signalling to Responding T Cells Is Key to Calcitonin Gene-Related Peptide-Exposed Endothelial Cell Enhancement of Th17 Immunity During Langerhans Cell Antigen Presentation.

Calcitonin gene-related peptide (CGRP) biases Langerhans cell (LC) Ag presentation to CD4+ T cells towards Th17-type immunity through actions on endothelial cells (ECs). We now report further evidence that IL-6 signalling at responding T cells mediates this effect. This CGRP effect was absent with ECs from IL-6 KO mice. Exposure of LCs, but not T cells, to IL-6 enhanced IL-6 and IL-17A production and reduced IFN-γ in the T-cell response. Pretreatment of LCs with IL-6 receptor α-chain (IL-6Rα) antibodies prior to IL-6 exposure significantly inhibited these responses. However, T-cell pretreatment with an IL-6/IL-6Rα chimera mimicked the effect of IL-6 pretreatment of LCs on T-cell responses. When this experiment was performed in the presence of the ADAM17 and ADAM10 inhibitor TAPI-1 during LC pretreatment of LCs and during the Ag presentation culture, release of soluble IL-6Rα chains into the medium was very significantly reduced, but this did not affect levels of T-cell cytokine release. Interestingly, LC exposure to IL-6 significantly increased LC IL-6 expression. Furthermore, pretreatment of T cells with antibodies against the IL-6 receptor β-chain significantly inhibited the IL-6 effect. CGRP may stimulate ECs in lymphatics and/or lymph nodes to produce IL-6 which likely results in migrating LCs nonclassically presenting IL-6. Furthermore, we found that IL-6 induces IL-6 production by LCs, suggesting an autocrine amplification pathway for this effect.

The relationship between elevated serum levels of soluble interleukin-2 receptor and renal outcomes in hemophagocytic lymphohistiocytosis

BACKGROUND: Hemophagocytic lymphohistiocytosis is an uncommon disease with a high mortality rate due to ineffective overactivation of the immune system. THE AIM: to assess the effect and prediction of elevated serum soluble interleukin-2 alpha level on kidney outcomes in hemophagocytic lymphohistiocytosis.PATIENTS AND METHODS: In this analytic (experimental) clinical studies type with randomized clinical trials design in meta-analysis article, two-hundred eighty-three patients with hemophagocytosis lymphohistiocytosis diagnosis and kidney impairment were investigated.RESULTS: Relative risk and Odds ratio of elevated serum soluble interleukin-2 receptor alpha level on kidney failure progression to kidney replacement therapy was assessed 1.04 and 1.12 during 28 days and interquartile range of 35.5 days in hemophagocytic lymphohistiocytosis in this research. In prediction probability of death and chronic kidney disease progression to end-stage kidney disease led to kidney replacement therapy as outcome using high serum soluble interleukin-2 receptor alpha level was not significant statistically (p-value of 0.91 and p=0.56, respectively). There was strong negative correlation between soluble interleukin-2 receptor alpha levels and cumulative incidence of renal outcomes such as hyponatremia, proteinuria, acute kidney disease, elevated serum blood urea nitrogen and serum creatinine levels with rs of -0.7 and p-value of o.18. There was relationship between serum soluble interleukin-2 receptor alpha level and past medical history (p-value: 0.01) but overall this analysis did not show significant level statistically (p-value: 0.1).CONCLUSION: There was a strong negative correlation between serum soluble interleukin-2 receptor alpha levels and cumulative incidence of renal outcomes. There wasn't a relationship between serum soluble interleukin-2 receptor alpha level and renal outcome after adjustment of confounding factors for renal function except for past medical history.Sujpplement files (Tables) are located at: https://figshare.com/authors/Fateme_Shamekhi_Amiri/9040742

Proinflammatory cytokine genes and their polymorphic variants: clinical and laboratory profiles in the Federal Firefighting Service employees of the EMERCOM of Russia

Relevance. Genetic determinants of multifactorial diseases are critical for assessing the risk of genetic diseases and their prevention, especially among the workforce exposed to industry-related dangerous and aggressive occupational factors. Firefighters perform combat service duties in extremely unfavorable industrial environments associated with occupational diseases. Respiratory diseases are among the pathologies with highest incidence rates in firefighters. In addition to environmental factors, the development of these diseases (especially bronchial asthma and chronic obstructive pulmonary disease) is largely driven by impaired immune system – one of the three critical regulatory systems involved in pathogenetic mechanisms of various diseases, including inflammatory diseases. Polymorphic gene variants of inflammatory mediators – in particular cytokine genes and their receptors – mediate the immune system activity and can impact its functionality, susceptibility, or resistance to disease development.The objective is to analyze how interleukin 1β, 4, 6, 13, TNF and interleukin 6 receptor genes, as well as their polymorphic variants are associated with respiratory diseases and changes in the biomarker profiles showing immune response intensity in the employees of the Federal Firefighting Service of the EMERCOM of Russia. Methodology. Molecular genetic profiling and immunology tests were performed in 70 employees of the Federal Firefighting Service of the EMERCOM of Russia to analyze proinflammatory cytokine genes and their polymorphic variants. Real-timePCR was used to analyze the interleukin 1β, 4, 6, 13, TNF and interleukin-6 receptor genes and their polymorphic variants. Immunological examination evaluated the blood monocyte subpopulations and relative count of type 2 T-helper cells; flowcytometry and immunochemiluminescence assays were used to evaluate immune response biomarkers in peripheral blood and total immunoglobulin E (IgE) respectively.Results and discussion. The analysis provides evidence that minor alleles of most polymorphic cytokine genes are associated with a proinflammatory phenotype, which is especially apparent for genotypes comprising several minor alleles. Allele A at rs1 800 629 polymorphic TNF gene exposed a direct correlation with respiratory diseases, as well as with increased monocyte differentiation. Allele T of IL4 rs2243250 gene and allele A of IL1β rs16944 gene were associated with increased proinflammatory monocyte count. Elevated count of type 2 T-helper mediators of humoral response, especially of allergicorigin, was observed in individuals with C/C IL6 rs1 800 795 and G/G IL1β rs16944 genotype.Conclusion. The obtained results suggest that evaluation of cytokine gene polymorphic variants is a promising strategy to predict the risk of respiratory diseases in firefighters. Prompt assessment of genetic predisposition to a proinflammatory phenotype paves the way towards prevention and early detection of inflammatory diseases in this cohort of workers.

IL-9 as a naturally orthogonal cytokine with optimal JAK/STAT signaling for engineered T cell therapy.

Arming T cells with a synthetically orthogonal IL-9 receptor (o9R) permits facile engraftment and potent anti-tumor functions. We considered whether the paucity of natural IL-9R expression could be exploited for T cell immunotherapy given that, in mice, high doses of IL-9 were well-tolerated without discernible immune modulation. Compared to o9R, T cells engineered with IL-9R exhibit superior tissue infiltration, stemness, and anti-tumor activity. These qualities are consistent with a stronger JAK/STAT signal, which in addition to STAT1/3/5, unexpectedly includes STAT4 (canonically associated with IL-12 but not common γ-chain cytokines). IL-9R T cells are exquisitely sensitive to perturbations of proximal signaling, including structure-guided attenuation, amplification, and rebalancing of JAK/STAT signals. Biased IL-9R mutants uncover STAT1 as a rheostat between proliferative stem-like and terminally differentiated effector states. In summary, we identify native IL-9/IL-9R as a natural cytokine-receptor pair with near-orthogonal qualities and an optimal JAK/STAT signaling profile for engineered T cell therapy.

IL-25 Enhances B Cell Responses in Type 2 Inflammation Through IL-17RB Receptor.

Alarmin cytokine IL-25 promotes type 2 inflammatory responses in disorders such as asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) and known targets include ILC2 and Th2 cells. However, other cellular targets for IL-25 remain poorly defined. To investigate induction and expression of IL-25 receptor (IL-17RB) by B cells and evaluate responsiveness of IL-17RB-expressing B cells to IL-25 invitro. IL-17RB expression, regulation and function on B cells were evaluated in peripheral blood-derived B cells by flow cytometry and RT-PCR, including in response to IgE-inducing stimuli (anti-CD40 mAb and IL-4). Single-cell RNA sequencing was used to compare IL-17RB+ and IL-17RB-activated peripheral blood-derived B cells. To evaluate B cell IL-17RB expression within type 2 inflamed tissue, B cells were compared from nasal polyps, control turbinate tissue and matched peripheral blood. Activation of B cells with anti-CD40 and IL-4 increased IL-17RB expression at both protein and mRNA level, which was further upregulated by IL-25. B cells induced to express IL-17RB responded to IL-25 with enhanced antibody production. Single-cell RNA-sequencing showed that IL17RB+ activated B cells expressed higher levels of IGHE, CCL17 and CCL22 compared to IL17RB- B cells. B cells from nasal polyp tissue expressed higher levels of surface IL-17RB compared with control tissue, correlating with patient-reported CRSwNP severity (SNOT-22). Peripheral blood B cells activated under IgE-inducing conditions express surface IL-17RB, and tissue IL-17RB+ B cells are increased in type 2 inflammation. IL-17RB+ cells have a distinct transcriptional profile and respond to IL-25 with enhanced antibody production, highlighting the IL-25/IL-17RB pathway as a potential therapeutic target for CRSwNP and other type 2 inflammatory disorders.

IL-7 secreted by keratinocytes induces melanogenesis via c-kit/MAPK signaling pathway in Melan-a melanocytes.

Abnormal melanin synthesis within melanocytes can result in pigmentary skin disorders. Although pigmentation alterations associated with inflammation are frequently observed, the precise reason for this clinical observation is still unknown. More specifically, although many cytokines are known to be critical for inflammatory skin processes, it is unclear how they affect epidermal melanocyte function. Here, we wanted to see how IL-7, a type I cytokine, affects melanocytes because cytokine is known to be associated with various skin diseases. To this end, Melan-a melanocytes were tested for expression of the IL-7 receptor α (IL-7Rα) and common gamma chain (γc) and their response to IL-7. IL-7 promotes melanogenesis in Melan-a melanocytes, resulting in increased intracellular tyrosinase activity and melanin content. It also upregulates the transcription of melanogenesis-related genes like MITF, tyrosinase, TRP1, and TRP2. IL-7 receptor α (IL-7Rα) and common gamma chain (γc) are interacted with c-kit in Melan-a melanocytes. IL-7 also activates the phosphorylated c-kit and its downstream target genes, such as ERK1/2, JNK, and p38 phosphorylation in Melan-a melanocytes. Furthermore, inhibition of c-kit by ISCK03, c-kit inhibitor, significantly reversed c-kit phosphorylation and MITF expression. We also showed that IL-7 induces melanogenesis via the c-kit/MAPK signaling pathway based on the findings of this study. In conclusion, Melan-a melanocytes express IL-7 receptors on their surface, and IL-7 treatment on Melan-a cells leads to melanogenesis via the c-kit/MAPK signaling pathway. These results could lead to new treatments for pigmentation disorders and provide insight into the immunological processes surrounding melanocytes.

Exploring the effect of hsa-miR-19b-3p on IL-1R1 expression and serum levels in alopecia areata.

Alopecia areata (AA) is an autoimmune condition marked by hair loss, linked to inflammatory processes involving the interleukin-1 receptor type 1 (IL-1R1) pathway. This study aims to explore the relationship between IL-1R1 gene expression, serum IL-1R1 levels, and hsa-miR-19b-3p in relation to AA severity. Using a case-control design, we assessed 100 AA patients and 100 healthy controls, measuring serum IL-1R1 through enzyme-linked immunosorbent assay (ELISA) and analyzing IL-1R1 gene and hsa-miR-19b-3p expression levels via quantitative real-time PCR (qRT-PCR). Bioinformatic analysis predicted a binding site for hsa-miR-19b-3p on the IL-1R1 gene, suggesting a regulatory role for this miRNA in AA pathology. Demonstrated significantly higher serum IL-1R1, IL-1R1 gene expression, and hsa-miR-19b-3p levels in AA patients compared to controls. Within the AA cohort, severe cases showed the highest levels, with notable correlations between serum IL-1R1, IL-1R1 gene expression, and hsa-miR-19b-3p. Receiver Operating Characteristic (ROC) curve analysis revealed robust diagnostic potential, with area under the curve (AUC) values of 0.71, 0.73, and 0.76 for serum IL-1R1, hsa-miR-19b-3p, and IL-1R1 gene expression, respectively. Elevated IL-1R1 and hsa-miR-19b-3p levels are associated with AA and its severity, suggesting these markers have potential as diagnostic and prognostic indicators. These findings enhance the understanding of IL-1R1's role in AA and highlight potential molecular targets for future therapeutic approaches.

IL-17 family members exert an autocrine pro-inflammatory loop in CF respiratory epithelial cells ex vivo.

Lungs of people with Cystic Fibrosis (pwCF) are characterized by chronic inflammation and infection with P. aeruginosa. High levels of IL-17A and F have been observed in sputum of pwCF and the interleukin-17(IL-17) family (A-to-F) has been suggested to play a key role in CF pulmonary disease. We measured mRNA levels of IL-17 receptors (IL-17R) by RT-qPCR in CF bronchial epithelial (CFBE) cultured cells upon infection with P. aeruginosa PAO1 strain or clinical exoproducts (EXO) isolated from pwCF. We measured IL-17 mRNA expression by RT-qPCR and the release of cytokines by ELISA and Bioplex from CF primary nasal epithelial (HNE) cultured cells. Infection of CFBE cells with PAO1 or EXO isolated from 15 pwCF significantly increased mRNA expression of all IL-17R, except IL-17RD. Infection of HNE cells with EXO isolated from the correspondent donor significantly increased the mRNA levels of all the IL-17 cytokines and receptors, except for IL-17D and IL-17RD, and the release of the cytokines IL-17A, IL-17B, IL-17C, IL-17E and IL-17F. HNE exposed to IL-17A and F were induced to release pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), neutrophil chemokines (IL-8, G-CSF) and cytokines known to be involved in chloride and bicarbonate secretion, together with mucin upregulation (IL-4, IL-13). These results highlight a wider expression of IL-17 family member in respiratory epithelial cells, which can play a role as an autocrine inflammatory amplification loop in CF airways. These in-vitro studies using patient-derived cultures underline the relevant role of IL-17 family members in CF pulmonary immune response.

A real-world Pharmacovigilance study of brodalumab based on the FDA adverse event reporting system

Brodalumab, a humanized monoclonal antibody that targets the interleukin-17 receptor A, is primarily used to manage moderate-to-severe plaque psoriasis. Although it has demonstrated favorable efficacy and safety in clinical trials, the strict inclusion and exclusion criteria may not fully reflect its safety profile in real-world settings. As its use becomes more widespread in clinical practice, understanding its safety in real-world applications is crucial.This study employed disproportionality analysis to assess the safety of brodalumab by examining all adverse event reports that identified brodalumab as the primary suspected drug in the FDA Adverse Event Reporting System database since 2017. Techniques such as the Reporting Odds Ratio, Proportional Reporting Ratio, Multi-item Gamma Poisson Shrinker, and Bayesian Confidence Propagation Neural Network were utilized to analyze the adverse events associated with brodalumab. Additionally, the Weibull distribution was used to model the temporal risk of adverse events.The study identified several adverse reactions already listed on the drug’s label that showed positive signals, including arthralgia, headache, myalgia, suicidal ideation, oropharyngeal pain, injection site mass, and infections. Additionally, we found potential adverse reactions not noted on the drug’s label that exhibited positive signals, including depression, increased blood pressure, peripheral swelling, gait disturbance, inability to walk, stress, myocardial infarction, sepsis, uveitis, nephrolithiasis, and interstitial lung disease. Moreover, this analysis highlighted the critical need for vigilant monitoring of adverse events, especially during the first month following the initiation of treatment.This study provides initial insights into the real-world safety of brodalumab, confirming known adverse reactions and uncovering additional potential risks. The results deliver vital information that can assist clinicians in making informed decisions when prescribing brodalumab for psoriasis treatment.

The High-Affinity IL-2 Receptor Affects White Matter Damage after Cerebral Ischemia by Regulating CD8 + T Lymphocyte Differentiation.

IL-2/IL-2R inhibition improved the prognosis of ischemic stroke by regulating T cells, while the respective contribution of T cells with high/medium/low-affinity IL-2 receptors remained unclear. Single-cell RNA sequencing data of ischemic brain tissue revealed that most of the high-affinity IL-2R would be expressed by CD8 + T cells, especially by a highly-proliferative subset. Interestingly, only the CD8 + T cells with high-affinity IL-2R infiltrated ischemic brain tissues, highly expressing 32 genes (including Cdc20, Cdca3/5, and Asns) and activating 7 signaling pathways (including the interferon-alpha response pathway, a key mediator in the proliferation, migration, and cytotoxicity of CD8 + T cells). Its interaction with endothelial cells and the ligand-receptor interaction analysis also suggested an augmented brain infiltration after cerebral ischemia. In IL-2Rα KO mice, who would have no high- or low-affinity IL-2R in CD8 + T cells, the RNA-seq, qPCR, immunofluorescence, and multiplex assays found that the expression of CD8b, CD122, CD132, and Vcam-1 was upregulated in the acute phase of cerebral ischemia, with decreasing H2-k1 positive cells and increasing Vcam-1 and CD8b positive cells in brain tissue. However, inflammation pathways in brain were inhibited and peripheral inflammatory cytokine levels were reduced, indicating that CD8 + T cells changed into an anti-inflammatory phenotype. The IL-2Rα KO mice after cerebral ischemia also performed better in behavioral tests and had more favorable results in diffusion tensor imaging, electrophysiology, and MBP testing. Our findings suggested that the CD8 + T cells with high-affinity IL-2R, as well as IL-2Rα, might be targeted to improve the clinical management of ischemic stroke.

Targeting Fibroblast-Derived Interleukin 6: A Strategy to Overcome Epithelial-Mesenchymal Transition and Radioresistance in Head and Neck Cancer.

Cancer-associated fibroblasts have been reported to play a central role in driving cancer progression, promoting metastasis, and conferring resistance to therapy in HNSCC. Indirect and direct co-culture models of HPV-positive and HPV-negative HNSCC cells with fibroblasts were developed to study the effect of fibroblasts on cancer cells. ELISA was used to measure IL-6 secretion in these models. To dissect the underlying signalling mechanisms, the effects of IL-6, an IL-6 receptor (IL-6R) inhibitor, a MAPK/ERK inhibitor, and a JAK/STAT inhibitor were evaluated. Epithelial-to-mesenchymal transition (EMT) was assessed by measuring EMT markers and conducting scratch assays and spheroid assays. Radioresistance was evaluated using clonogenic assays. Additionally, radioresistant (RR) cell lines were established from parental cells to examine the correlation between radioresistance and EMT. Fibroblasts were found to drive EMT-like changes and heightened radioresistance in HNSCC cells through IL-6 secretion. Remarkably, these Fb-driven effects were robustly reversed using IL-6R and MAPK/ERK inhibitors in both HPV-positive and HPV-negative cell lines, whereas JAK/STAT inhibitors proved effective only in HPV-negative cells. RR cell lines exhibit a more aggressive phenotype than their parental counterparts, marked by pronounced EMT features and heightened resistance to radiotherapy. Importantly, these aggressive characteristics were substantially attenuated by targeting IL-6R or MAPK/ERK pathways. This study highlights the critical role of fibroblast-secreted IL-6 in driving and maintaining EMT and radioresistance in HNSCC, resulting in a more aggressive tumour phenotype. Targeting the IL-6/IL-6R/ERK pathway emerges as a promising therapeutic approach for combating CAF-driven tumour progression and improving clinical outcomes in patients with aggressive, therapy-resistant HNSCC.

Current landscape and future prospects of interleukin-2 receptor (IL-2R) agonists in cancer immunotherapy

ABSTRACT Immune checkpoint blockade (ICB) has significantly improved the survival for many patients with advanced malignancy. However, fewer than 50% of patients benefit from ICB, highlighting the need for more effective immunotherapy options. High-dose interleukin-2 (HD IL-2) immunotherapy, which is approved for patients with metastatic melanoma and renal cell carcinoma, stimulates CD8+ T cells and NK cells and can generate durable responses in a subset of patients. Moreover, HD IL-2 may have potential efficacy in patients whose disease has progressed following ICB and plays a vital role in expanding tumor-infiltrating lymphocyte (TIL) in TIL therapy. Despite its potential, the use of HD IL-2 is limited by severe toxicities such as hypotension and vascular leak syndrome. Additionally, only a few patients achieve a good outcome after HD IL-2 therapy. To address these challenges, numerous next-generation IL-2 receptor (IL-2 R) agonists have been developed to exhibit treatment effects while minimizing adverse events. This review will explore IL-2 biology, the clinical application of HD IL-2 therapy, and the development of novel IL-2 R agonists for cancer immunotherapy.

Terminal complement complex deposition on chondrocytes promotes premature senescence in age- and trauma-related osteoarthritis.

The complement system is locally activated after joint injuries and leads to the deposition of the terminal complement complex (TCC). Sublytic TCC deposition is associated with phenotypical alterations of human articular chondrocytes (hAC) and enhanced release of inflammatory cytokines. Chronic inflammation is a known driver of chondrosenescence in osteoarthritis (OA). Therefore, we investigated whether TCC deposition contributes to stress-induced premature senescence (SIPS) during aging in vivo and after ex vivo cartilage injury. Femoral condyles of male 13-week-old and 72-week-old CD59-ko (higher TCC deposition), C6-deficient (insufficient TCC formation), and C57BL/6 (WT) mice were collected to assess age-related OA. Furthermore, macroscopically intact human and porcine cartilage explants were traumatized and cultured with/without 30% human serum (HS) to activate the complement system. Explants were additionally treated with clusterin (CLU, TCC inhibitor), N-acetylcysteine (NAC, antioxidant), Sarilumab (IL-6 receptor inhibitor), STAT3-IN-1 (STAT3 inhibitor), or IL-1 receptor antagonist (IL-1RA) in order to investigate the consequences of TCC deposition. Gene and protein expression of senescence-associated markers such as CDKN1A and CDKN2A was determined. In the murine aging model, CD59-ko mice developed after 72 weeks more severe OA compared to C6-deficient and WT mice. mRNA analysis revealed that the expression of Cdkn1a, Cdkn2a, Tp53, Il1b, and Il6 was significantly increased in the cartilage of CD59-ko mice. In human cartilage, trauma and subsequent stimulation with HS increased mRNA levels of CDKN1A, CDKN2A, and IL6, while inhibition of TCC formation by CLU reduced the expression. Antioxidative therapy with NAC had no anti-senescent effect. In porcine tissue, HS exposure and trauma had additive effects on the number of CDKN2A-positive cells, while Sarilumab, STAT-IN-1, and IL-1RA reduced CDKN2A expression by trend. Our results demonstrate that complement activation and consequent TCC deposition is associated with chondrosenescence in age-related and trauma-induced OA. We provided evidence that the SIPS-like phenotype is more likely induced by TCC-mediated cytokine release rather than oxidative stress. Overall, targeting TCC formation could be a future approach to attenuate OA progression.

Expert Clinical Management of Inflammatory Immune-Related Arthritis in Patients with Cancer Receiving Immune Checkpoint Inhibitors.

Treatment guidelines for immune-related inflammatory arthritis (irAE-IA) in patients with cancer receiving immune checkpoint inhibitors (ICIs) are vague with respect to the use of specific agents. Patients are usually referred to rheumatologists for treatment. We conducted a survey of expert rheumatologists to determine current practices. We also assessed experts' views on the potential deleterious effects of various agents on tumor progression. We conducted a survey of international experts in the treatment of irAE-IA, identified as members of collaborative scientific workgroups in this area. Experts were presented with a case of a patient with moderate irAE-IA and were asked about their preferred management including glucocorticoids, timing and initial choice of disease-modifying antirheumatic drugs (DMARDs), and perception of the deleterious effects of different agents on tumor progression. We approached 25 experts, of whom 19 (76%) responded. Most experts (63%) agreed on 20 mg or less of prednisone as initial dose. Experts selected methotrexate (41%) or tumor necrosis factor inhibitor (TNFi) (23%) as the initial DMARD if there was no improvement with corticosteroids; most experts (42%) would initiate DMARDs after 4 weeks. For patients whose initial DMARD therapy failed, the second choice was either a tumor necrosis factor inhibitor (TNFi) (38%) or interleukin-6 receptor antagonist (IL6ri) (33%). Experts were most concerned about the potential deleterious effects on tumor progression of abatacept and prednisone at doses of 20 mg or higher. There was substantial heterogeneity in the initial management of irAE-IA. Further understanding of the pathophysiology of this immunotoxicity can assist in the classification of different presentations, selection of relevant outcomes, and planning of clinical trials to establish optimal therapeutic efficacy while minimizing potential deleterious effects of treatment on immune tumor responses.

Plant-derived Pembrolizumab in conjugation with IL-15Rα-IL-15 complex shows effective anti-tumor activity.

Anti-programmed cell death 1 (PD-1) monoclonal antibodies (mAbs) have proven to be effective in treating various cancers, including colorectal, lung, and melanoma. Despite their clinical success, some patients develop resistance to mAbs, requiring co-treatments with radio- or chemotherapy. Interleukin-15 (IL-15) is an immunostimulatory cytokine that promotes immune cell production and proliferation. It has been combined with mAbs and other immunotherapies to improve efficacy and reduce side effects. Fusion of anti-PD-1 mAb and IL-15 streamlines drug administration and management. In this study, we developed a prototype by conjugating the IL-15 receptor subunit alpha (IL-15Rα) and IL-15 complex to the C-terminus of anti-PD-1 Pembrolizumab (Pembrolizumab-IL-15Rα-IL15) using plant molecular farming for production. LC-MS revealed the presence of plant N-glycans (GnGnXF, GnXF and Man9GlcNAc2) on the molecule, which may affect receptor-binding avidity. However, ELISA demonstrated comparable binding efficacy of Pembrolizumab-IL-15Rα-IL15 to human PD-1 protein as commercial Pembrolizumab. In a mouse anti-cancer study, Pembrolizumab-IL-15Rα-IL15 (3 mg kg-1) exhibited slightly improved tumor-growth inhibition, reducing tumor size by 94% compared to commercial Pembrolizumab (5 mg kg-1) with an 83% reduction, regardless of statistically significant difference. In conclusion, Pembrolizumab-IL-15Rα-IL-15 was successfully produced using plant molecular farming and shows promise in addressing mAb drug resistance and enhancing the immunomodulatory effects of IL-15 payload.

Off-Label Use of Anakinra in Inflammatory Conditions in Neonates and Infants Up to 3 Months of Age: A Case Series and a Review of the Literature.

Anakinra is an interleukin-1 receptor antagonist (IL-1Ra). Since IL-1 has been shown to play a key role in the etiology of different autoinflammatory diseases, blocking its pathway has become an important therapeutic target, even in neonates. We aimed to report our experience in using anakinra to treat specific neonatal inflammatory conditions. We described the clinical management with anakinra of five cases of neonates or infants up to 3 months of age admitted to the neonatal intensive care unit (NICU) of Bambino Gesù Children's Hospital IRCCS in Rome (Italy) from 2020 onwards. Medical history and clinical data concerning NICU hospitalization were collected from the electronic medical records. Furthermore, we performed a literature review of off-label anakinra in the first 3 months of life, up to 5 April 2024. We excluded from this review cases of cryopyrin-associated periodic syndrome, deficiency of the interleukin-1 receptor antagonist, and mevalonate kinase deficiency, for which anakinra is a known treatment. We reported three off-label cardiorespiratory reasons to use IL-1Ra from our series: (i) chronic lung disease with pulmonary hypertension, (ii) interstitial lung disease with pulmonary hypertension to facilitate the weaning from respiratory support, and (iii) post-surgical polyserositis if effusions accumulate despite drainage. In all our patients, the drug was administered at a dosage of 10mg/kg/day. The route of administration was chosen based on the patient's clinical characteristics, with the subcutaneous and intravenous routes being comparable in efficacy. The duration of therapy was modulated based on the patient's clinical response, with a minimum duration of 4 months. A total of 308 retrieved articles were screened, and then full texts of records deemed eligible for inclusion were assessed. Based on the literature search and our five cases, a total of 17 infants were treated with anakinra outside its approved indications. The major off-label use was for hemophagocytic lymphohistiocytosis/macrophage activation syndrome, followed by multisystem inflammatory syndrome in children and Kawasaki disease, as in two of our cases. According to the results of our case series and review of the literature, the off-label use of anakinra in neonates with inflammatory conditions refractory to first-line therapy could be considered. Prospective, multicenter research is necessary to determine whether anakinra is a safe treatment option for these infants to prevent early inflammatory illnesses and in which situations it could enhance clinical results.

Correlates and Consequences of Clonal Hematopoiesis Expansion Rate: A 15-Year Longitudinal Study of 6,986 Women.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased mortality and malignancy risk, yet the determinants of clonal expansion remain poorly understood. We performed sequencing at >4,000x depth of coverage for CHIP mutations in 6,986 postmenopausal women from the Women's Health Initiative at two timepoints approximately 15 years apart. Among 3,685 mutations detected at baseline (VAF ≥ 0.5%), 50% progressed to CHIP (VAF ≥ 2%) at follow-up. We confirmed that clonal expansion is highly dependent on initial clone size and CHIP driver gene, with SF3B1 and JAK2 mutations exhibiting the fastest growth rate. We identified germline variants in TERT , IL6R , TCL1A , and MSI2 that modulate clonal expansion rate. Measured baseline leukocyte telomere length showed differential effects on incident CHIP risk, with shorter baseline leukocyte telomere length predisposing to incident PPM1D mutations and longer baseline leukocyte telomere length favoring incident DNMT3A mutations. We discovered that the IL6R missense variant p.Asp358Ala specifically impairs TET2 clonal expansion, supported by direct measurements of soluble interleukin-6 receptor and interleukin-6. Faster clonal growth rate was associated with increased risk of cytopenia, leukemia, and all-cause mortality. Notably, CHIP clonal expansion rate mediated 34.4% and 43.7% of the Clonal Hematopoiesis Risk Score's predictive value for leukemia and all-cause mortality, respectively. These findings reveal key biological determinants of CHIP progression and suggest that incorporating growth rate measurements could enhance risk stratification.