Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the spine and pelvic bones. Recently, many researchers have confirmed that biological therapy is effective for AS patients, which provides a new perspective for the treatment of AS. This study aimed to evaluate the characteristics of scientific research on AS and biological therapy worldwide and investigate research hotspots and the direction of future trends. Global literature on AS and biological therapy published from 2004 to 2023 was searched in the Web of Science, Scopus, and PubMed databases. Visualization and bibliometric analysis were carried out using the VOSviewer and CiteSpace software with the retrieved data regarding countries, institutions, journals, authors, and keywords. A total of 2,243 related articles were included, showing that the number of articles in this field has increased annually. The highest number of articles were from the USA (24.39%), followed by Italy (14.36%), England (12.19%), Germany (10.66%), and Spain (7.86%). Braun J was the most prolific author, with a h-index of 16. The institution with the most articles was Charite Universitatsmedizin Berlin, and the Rheumatology journal had the highest number of publications. "janus kinase inhibitor" and "secukinumab" displayed a notable citation burst in recent years, indicating IL-17i and JAKi are research hotspots. More and more attention has been paid to the association between AS and biological therapy in the past two decades. The USA plays a leading role, and China has made remarkable progress. This study has provided a valuable reference for future research in this field.

Diabetes mellitus is a chronic disease that has become more prevalent worldwide because of lifestyle changes. It leads to serious complications, including increased atherosclerosis, protein glycosylation, endothelial dysfunction, and vascular denervation. These complications impair neovascularization and wound healing, resulting in delayed recovery from injuries and an elevated risk of infections. The present study aimed to investigate the effect of lipoic acid (LA) on the key mediators involved in the wound healing process, specifically CD4 + CD25 + T cell subsets, CD4 + CD25 + Foxp3 + regulatory T (Treg) cells, T-helper-17 (Th17) cells that generate IL-17 A, glucocorticoid-induced tumor necrosis factor receptor (GITR) expressing cells, as well as cytokines such as IL-2, IL-1β, IL-6, and TNF-α and IFN-γ. These mediators play crucial roles in epidermal and dermal proliferation, hypertrophy, and cell migration.

We divided mice into 5 groups: the non-diabetic (normal control; NC), wounded non-diabetic mice (N + W), wounded diabetic mice (D + W), wounded diabetic mice treated with 50 mg/kg lipoic acid (D + W + L50) for 14 days, and wounded diabetic mice treated with 100 mg/kg lipoic acid (D + W + L100) for 14 days.

Flow cytometric analysis indicated that lipoic acid-treated mice exhibited a significant decrease in the frequency of intracellular cytokines (IL-17 A, TNF-α and IFN-γ) in CD4 + T cells, as well as a reduction in the number of GITR-expressing cells. Conversely, a significant upregulation in the number CD4+, CD25+, FOXp3 + and CD4 + CD25 + Foxp3 + regulatory T (Treg) cells was observed in this group compared to both the normal + wounded (N + W) and diabetic + wounded (D + W) groups. Additionally, the mRNA Levels of inflammatory mediators (IL-2, IL-1β, IL-6, and TNF-α) were downregulated in lipoic acid-treated mice compared to other groups. T thereby he histological findings of diabetic skin wounds treated with lipoic acid showed well-healed surgical wounds.

These findings support the beneficial role of lipoic acid in fine-tuning the balance between anti-inflammatory and pro-inflammatory cytokines, influencing both their release and gene expression.

Sepsis, a condition of significant clinical concern, is characterized by life-threatening organ dysfunction that arises from an infection and is exacerbated by a dysregulated host response. Targeting immune modulation, particularly against tumor necrosis factor-alpha (TNF-α), has emerged as a promising anti-inflammatory therapeutic strategy. However, approaches such as blood purification to eliminate inflammatory mediators or the use of anti-TNF-α therapies have shown limited efficacy in clinical practice. This literature review aims to elucidate the pathogenesis of sepsis and dissect the factors contributing to unfavorable outcomes in TNF-α-targeted treatments. Our analysis highlights several potential reasons for therapeutic failure. Complete blockade of TNF-α may adversely affect both TNFR1 and TNFR2 signaling, thereby reducing the efficacy of TNF-α inhibitors. Additionally, the complex heterogeneity of sepsis, including the etiology of infection, patient-specific factors (e.g., immune responsiveness, body mass index, and obesity), the development of anti-drug antibodies, and treatment duration, significantly influences therapeutic outcomes. Based on these insights, we emphasize the need for precision medicine in sepsis management. This includes stratifying patients into subgroups, using TNFR2 agonists or TNFR1-specific antagonists, refining drug design, implementing multi-target combination therapies, and considering the patient's physiological state at the time of treatment. Collectively, these strategies could enhance the efficacy of sepsis management. This review underscores the multifaceted nature of sepsis treatment and highlights the imperative for personalized, multimodal therapeutic approaches to improve clinical outcomes.

Cytokines are crucial regulators of the immune system that orchestrate interactions between cells and, when dysregulated, contribute to the progression of chronic inflammation, cancer, and autoimmunity. Numerous biologic-based clinical agents, mostly monoclonal antibodies, have validated cytokines as important clinical targets and are now part of the standard of care for a number of diseases. These agents, while impactful, still suffer from limitations including a lack of oral bioavailability, high cost of production, and immunogenicity. Small-molecule cytokine inhibitors are attractive alternatives that can address these limitations. Although targeting cytokine-cytokine receptor complexes with small molecules has been a challenging research endeavor, multiple small-molecule inhibitors have now been identified, with a number of them undergoing clinical evaluation. In this review, we highlight the recent advancements in the discovery and development of small-molecule inhibitors targeting soluble cytokines. The strategies for identifying these novel ligands as well as the structural and mechanistic insights into their activity represent important milestones in tackling these challenging and clinically important protein-protein interactions.

Trihalomethanes (THMs), the major byproducts of water chlorination which are associated with various adverse health outcomes. However, the relationship of THMs with cardiovascular disease (CVD) in aging populations remains underexplored. We analyzed data from 5,400 participants in the National Health and Nutrition Examination Survey (NHANES) 2005-2012. Associations between blood THM concentrations and CVD were evaluated using weighted multivariable logistic regression. Weighted quantile sum (WQS) regression was applied to identify the most relevant THM components. We also performed mediation analysis to evaluate the role of inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), white blood cell count (WBC), and systemic inflammation response index (SIRI). Network toxicology analysis was used to explore the biological pathways linking THM exposure, CVD, and aging. Elevated blood concentrations of THMs, particularly chloroform (TCM) and total THMs (TTHMs), were significantly associated with increased odds of CVD. Stratified analyses revealed stronger associations among older adults, males, individuals with higher BMI, and those with hypertension. WQS regression identified TCM as the predominant contributor to the THM-CVD association, accounting for 58.0% of the mixture's effect. Mediation analysis showed that NLR partially mediated the association between TTHMs and CVD, explaining 7.12% of the total effect. Network toxicology analysis highlighted inflammation-related pathways, including the IL-17 signaling pathway, as key mechanisms linking THM exposure, CVD, and aging. Our study revealed elevated blood TCM and TTHM concentrations are associated with increased prevalence of CVD among U.S. adults aged 45 years and older. Network toxicology and mediation analysis suggest that systemic inflammation may play a mediating role in this relationship.

The increasing global aging population has brought greater focus to age-related diseases, particularly muscle-brain comorbidities such as sarcopenia and late-life depression. Sarcopenia, defined by the gradual loss of muscle mass and function, is notably prevalent among older individuals, while late-life depression profoundly affects their mental health and overall well-being. Epidemiological evidence suggests a high co-occurrence of these two conditions, although the precise biological mechanisms linking them remain inadequately understood. This review synthesizes the existing body of literature on sarcopenia and late-life depression, examining their definitions, prevalence, clinical presentations, and available treatments. The goal is to clarify the potential connections between these comorbidities and offer a theoretical framework for the development of future preventive and therapeutic strategies.

Stroke-induced opposite T-cell responses in the peri-lesion area and periphery worsen stroke outcomes by aggravating brain injury or increasing infectious complications, respectively. Despite their well-known role in T lymphocyte activation, the impact of TCRs (T-cell receptors) on stroke remains poorly understood. In this study, we investigated the causal link between TCRs and the opposite T-cell responses observed in intracerebral hemorrhage (ICH).

We established the ICH model by injecting the collagenase VII-S into the left striatum of young adult (10-12 weeks) male and female and aged (18-20 months) male C57BL/6 mice. We intraperitoneally administered AX-024, a small molecule inhibitor of TCR signaling, and evaluated the results using flow cytometry, Western blotting, immunofluorescence staining, histological staining, bacterial culture, and behavioral tests.

Our findings in young adult male mice indicate that administering AX-024 within 48 hours suppressed the activation of nonspecific and antigen-specific CD3 (cluster of differentiation 3)+CD4+ and CD3+CD8+ cells in the brain 36 hours and 3 days after ICH but not 7 days after. Additionally, it temporarily inhibited antigen-specific T-cell activation in the periphery at the above 2 time points. It also reduced molecular and cellular neuroinflammation in the hemorrhagic brain early after ICH. These effects in the brain and periphery of young adult male mice ultimately improved ICH outcomes while having no impact on lung bacterial loads. This can be further supported by similar findings in young adult female and aged male mice with ICH.

AX-024 may represent a promising option for mitigating the detrimental effects of T cells entering the damaged brain without increasing bacterial loads in the lung in ICH. The potential of AX-024 as a potent immunosuppressive treatment for ICH is an exciting prospect that warrants further investigation.

Mesangial proliferative glomerulonephritis (MsPGN) is a common form of glomerulonephritis characterized by mesangial cell proliferation and inflammatory responses. However, current clinical treatment options for MsPGN are rather limited. Oleanolic acid (OA), a natural pentacyclic triterpenoid compound, exhibits anti-tumor and anti-inflammatory properties and has been proven to have renal protective effects. We speculate that OA could potentially serve as an alternative therapy for MsPGN.

This study aimed to investigate the therapeutic efficacy and mechanism of OA against MsPGN.

Tail vein injection of anti-Thy1 antibody was used to establish the MsPGN model, followed by a comprehensive assessment of the effects of OA on renal function, histopathological changes, and inflammatory responses in anti-Thy1 nephritis rats. Subsequently, network pharmacology was employed to predict the key targets and pathways of OA in treating MsPGN. Finally, in vivo and in vitro experiments were conducted to validate the results of network pharmacology.

OA significantly improved renal function, and attenuated mesangial cell proliferation and inflammatory reactions in anti-Thy1 nephritis rats. Network pharmacology analysis identified TNF-α, IL-6, IL-1β, MAPK3, and AKT1 as key targets of OA in the treatment of MsPGN, and involved the IL-17 signaling pathway. Additionally, we observed increased phosphorylation levels of ERK and AKT, as well as activation of downstream inflammatory responses, in both anti-Thy1 nephritis rats and mesangial cells stimulated with IL-17. In contrast, treatment with OA and the ERK inhibitor PD98059 reversed these effects. Furthermore, we identified IL17RA within this pathway as a potential target of OA.

Our study demonstrates that OA can modulate the IL-17/ERK/AKT signaling pathway, thereby improving anti-Thy1 antibody-induced MsPGN. This establishes a theoretical basis for OA to potentially serve as a therapeutic agent for treating MsPGN.

Intricate interactions between immune cells and cytokines define psoriasis, a chronic inflammatory skin condition that is immunological-mediated. Cytokines, including interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), chemokines, and transforming growth factor-β (TGF-β), are essential for controlling cellular activity and immunological responses, maintaining homeostasis and contributing to the pathogenesis of psoriasis. These molecules modulate the immune microenvironment by either promoting or suppressing inflammation, which significantly impacts therapeutic outcomes. Recent research indicates that treatment strategies targeting cytokines and chemokines have significant potential, offering new approaches for regulating the immune system, inhibiting the progression of psoriasis, and reducing adverse effects of traditional therapies. This review consolidates current knowledge on cytokine and chemokine signaling pathways in psoriasis and examines their significance in treatment. Specific attention is given to cytokines like IL-17, IL-23, and TNF-α, underscoring the necessity for innovative therapies to modulate these pathways and address inflammatory processes. This review emphasizes the principal part of cytokines in the -pathological process of psoriasis and explores the challenges and opportunities they present for therapeutic intervention. Furthermore, we examine recent advancements in targeted therapies, with a particular focus on monoclonal antibodies, in ongoing research and clinical trials.

Sodium propionate (SP) has been shown to enhance alveolar growth retardation in Bronchopulmonary Dysplasia (BPD), but the mechanism remains unclear. The aim of this study is to explore the potential mechanism of SP in the treatment of BPD by utilizing animal and cell models along with bioinformation analysis. Neonatal mice were exposed to either air (21% O2) or hyperoxia (85% O2) from the first day after birth to establish the BPD model. The neonatal mice were intraperitoneally injected with normal saline (control group) or SP (500 mg/kg, SP group) from day 8 to day 14. SP significantly reduced the inflammatory condition of alveolar septal thickening, and decreased the alveolar fusion and mitigated weight loss in BPD mice. ELISA results demonstrated that SP significantly inhibited the secretion of IL-17, IL-6 and TNFα. Transcriptome analysis confirmed that IL-17 signaling pathway is closely related to the therapeutic effects of SP on BPD. In addition, MX2, MMP10, IL-11, ZMAT4 and SEC1 genes were identified as key and potential targets involved in the mechanism of SP treating BPD. Meanwhile, in mouse alveolar epithelial cells, apoptosis was induced by hyperoxia, but it was reduced following SP intervention. The expression of IL-17 pathway related genes: IL-17A, IL-6, TNFα and cox2 was decreased in hyperoxia treated cells after SP intervention. In conclusion, through transcriptome analysis, animal and cell experiments, we explored the role of sodium propionate in attenuating apoptosis in a BPD model through IL-17 pathway.

Rejection is a primary cause of allograft dysfunction after kidney transplantation. The diversity of immune subpopulations involved in the different endotypes of rejection remains to be delineated at single-cell resolution. In a cohort of 76 kidney transplant recipients, we conducted high-dimensional immune phenotyping of blood CD4 T and B cells, single-cell RNA and T/B cell receptor sequencing, and plasma cytokine profiling. Phenotypic, transcriptional, and clonal states of CD4T and B cells could significantly distinguish stable allograft states from rejection. Patients undergoing T cell-mediated rejection displayed accumulation of clonally expanded cytotoxic T helper (Th)1 cells and Th17-like cells, associated with predominant naive B cell responses. In contrast, antibody-mediated rejection was characterized by clonal expansion of Th1-polarized T follicular helper cells and effector T-bet+ memory B cells, both of which strongly expressed interleukin 12 and tumor necrosis factor-signaling pathways. Plasma cytokine analysis confirmed mixed Th1/Th17 and Th1/T follicular helper cell-driven inflammatory profiles distinguishing T cell-mediated rejection and antibody-mediated rejection, respectively. CD4T and B cell subpopulations and signatures were validated using bulk RNA-seq analysis of matched kidney allografts and using an independent single-cell RNA-seq data set. These data improve mechanistic understanding of the immune pathogenesis of rejection and support the development of more specific immunosuppressive therapies to treat allograft rejection.

Rheumatic heart disease (RHD) is an important and preventable cause of cardiovascular death and disability, but the lack of clarity about its exact mechanisms makes it more difficult to find alternative methods or prevention and treatment. We previously demonstrated that increased IL-17 expression plays a crucial role in the development of RHD-related valvular inflammatory injury. Macrophage autophagy/polarization may be a pro-survival strategy in the initiation and resolution of the inflammatory process. This study investigated the mechanism by which IL-17 regulates autophagy/polarization activation in macrophages. A RHD rat model was generated, and the effects of anti-IL-17 and 3-methyladenine (3-MA) were analyzed. The molecular mechanisms underlying IL-17-induced macrophage autophagy/polarization were investigated via in vitro experiments. In our established RHD rat model, the activation of the macrophage PINK1/Parkin autophagic pathway in valve tissue was accompanied by M1 macrophage infiltration, and anti-IL-17 treatment inhibited autophagy and reversed macrophage inflammatory infiltration, thereby attenuating endothelial-mesenchymal transition (EndMT) in the valve tissue. The efficacy of 3-MA treatment was similar to that of anti-IL-17 treatment. Furthermore, in THP-1 cells, the pharmacological promotion of autophagy by IL-17 induced M1-type polarization, whereas the inhibition of autophagy by 3-MA reversed this process. Mechanistically, silencing PINK1 in THP-1 blocked autophagic flux. Moreover, IL-17-induced M1-polarized macrophages promoted EndMT in HUVECs. This study revealed that IL-17 plays an important role in EndMT in RHD via the PINK1/Parkin autophagic pathway and macrophage polarization, providing a potential therapeutic target.

Chronic rhinosinusitis with nasal polyps (CRSwNPs) involves persistent sinus inflammation, with emerging evidence suggesting a potential role of rhinovirus (RV) in its pathophysiology. However, whether RV exists in nasal tissues and affects the nasal mucosa after the resolution of infection symptoms remains unknown.

To investigate the prevalence and impact of silent RV infection in nasal tissues.

RV loads were detected in the nasal tissues of 47 controls and 101 patients with CRSwNP without respiratory infection. Participants were categorized into RV-positive (+), RV-negative (-), and the "gray zone" groups. Quantitative polymerase chain reaction, Western blotting, and immunofluorescence assays were used to analyze the impact of silent RV infection on the immune status of nasal tissues.

Silent RV infection was prevalent in both control (34%) and CRSwNP (30.7%) tissues, with higher viral loads observed in the nasal polyps. In controls, it was associated with high expression of types 1 and 2 interferon (IFN), type 2 inflammation, interleukin (IL)-17A, and IL-10. In patients with CRSwNP, silent RV infection was associated with lower levels of type 1 IFN, IL-17A, type 2 inflammation, and IL-10 but higher levels of type 2 IFN compared with those without RV infection. Meanwhile, RV (+) nasal polyps exhibited fewer tissue eosinophils and neutrophils than RV (-) nasal polyps.

Silent RV infection was prevalent in the nasal tissues, with a higher viral load detected in the nasal polyps. This silent RV infection is associated with distinct immune responses in healthy controls and patients with CRSwNP, involving differential modulation of IFNs, TH2 cytokines, IL-17A, IL-10, and eosinophil and neutrophil levels.

Psoriasis, a chronic inflammatory skin disorder characterised by erythematous and scaly plaques, can be both physically and emotionally distressing for patients. Dead Sea climatotherapy (DSC), a treatment modality combining sun exposure, mineral-rich water and mud therapy during 4 weeks at Ein Gedi, Israel, is used for a small group of patients with psoriasis. This study aimed to investigate the cellular composition of psoriatic skin lesions at relapse after complete clearance from DSC. Skin biopsies from baseline, end of treatment and relapse were collected from eight patients with plaque psoriasis who achieved complete clearance from Dead Sea climatotherapy treatment. These biopsies were subjected to immunohistochemistry, RNA sequencing and quantitative polymerase chain reaction analysis (qPCR). Our findings demonstrate that DSC effectively reduces inflammatory markers to levels comparable to baseline non-lesional skin in the short term. The differential expression analysis identified several upregulated differentially expressed genes, including OSM, CXCL8, TREM1, CXCL1, CSF3R, BCL2A1 and CXCL2, in relapsed psoriasis skin compared with baseline lesional skin. These findings were confirmed by qPCR analysis. Pathway enrichment analysis indicated a marked upregulation of neutrophil-associated pathways in relapse skin compared with baseline lesional skin. Immunohistochemical staining for neutrophil markers, such as CD11b, CD15, CD66b, CD207, MPO and NE, showed a non-significant trend towards enhanced neutrophil infiltration and activation at relapse. In conclusion, while DSC provides short-term effectiveness in managing psoriasis, the initial relapse phase is associated with neutrophil activation and migration. Thus, targeting neutrophils early in the psoriasis disease course may disturb the evolution of psoriasis, potentially preventing disease chronicity.

Psoriasis is a chronic inflammatory skin disease characterized by dysregulation of the interleukin 17 (IL-17) signaling axis. Given that psoriasis development depends on keratinocyte stem cells and early progenitors' sensitivity to differentiation, we analyzed IL-17 ligands and the expression and function of in a novel subset of keratinocyte subpopulations: keratinocyte stem cells (KSC) and early and late Transit Amplifying (ETA or LTA, respectively) cells. We found that all subpopulations expressed all IL-17 variants, predominantly in ETA and LTA. Conversely, IL-17 receptor expression resulted in more heterogeneity, with IL-17RA, -C, and -E being the most differentially regulated. Stimulus with IL-17A, IL-17-F, IL-17-A/F, and IL-17C promotes the upregulation of CXCL1, CXCL8, and DEFB4 mRNAs expression in both KSC and ETA. Moreover, IL-17A and IL-17A/F mainly decrease KSC proliferation and promote cell cycle block. Globally, IL-17A and IL-17A/F modulated the expression of proliferation, differentiation, and psoriasis-associated markers. Furthermore, KSC- and ETA-derived 3D reconstructions displayed increased epidermal thickness and upregulated KRT16 expression after treatment with IL-17A or IL-17A/F. Therefore, our data demonstrated that IL-17 family members perform distinctive functions in a specific keratinocyte subpopulation and define IL-17 signaling as a critical modulator of KSC behavior, proving its role in epidermal homeostasis dysregulation of psoriasis.

Nuclear receptor retinoid-related orphan receptor gamma-t (RORγt) is a major transcription factor for Th17 cell differentiation and IL-17 production. RORγt has been considered as a promising drug target for the treatment of IL-17-mediated inflammatory diseases. Numerous small molecule inhibitors have been discovered, and more than 20 of RORγt inhibitors have been advanced to clinical trials. However, none of these compounds has yet achieved market approval.

This manuscript summarizes the development of 22 clinical-stage RORγt inhibitors, including their structures, patent applications, and clinical trial status, based on publications and patents available up to November 2024.

The discovery of RORγt inhibitors was considered as an exciting field for the development of small molecular treatments, which has gone through a boom period in the past 10 years. However, some of the leading RORγt inhibitors recently failed in clinical trials due to lack of efficacy or having some safety concerns, although a few small molecule candidates targeting RORγt are still in trials and more in preclinical studies. Realizing the challenge, researchers started to develop different approaches such as dual targeting or exploring new indications, utilizing the potential value of RORγt inhibitors.

Rheumatoid Arthritis (RA), a chronic inflammatory autoimmune condition, presents a substantial challenge to public health. Dictamnus dasycarpus Turcz. (D. dasycarpus) is a traditional Chinese medicinal plant recognized for its anti-inflammatory properties and is increasingly being utilized as a potential anti-RA agent, but the underlying mechanism is still unclear.

The objective of this research is to elucidate the potential active components and therapeutic properties of D. dasycarpus in experimental RA-induced DBA/1J mice, and to uncover the pharmacological basis of its action.

Surface plasmon resonance (SPR) was employed to ascertain the specificity of interactions between protein targets and D. dasycarpus active ingredients for treating RA. The extract of D. dasycarpus was obtained by HP-20 microresin column chromatography, and its chemical composition was assessed using UPLC-Orbitrap-MS. This study utilized a collagen-induced arthritis (CIA) mouse model for in vivo experimentation. Body weight, foot thickness measurements, arthritis scores, immune organ index, and serum antibody levels of mice were used as indicators to evaluate the effects of D. dasycarpus components in treating RA. The serum levels of inflammatory factors in mice were measured using a cytokine antibody microarray assay. Additionally, this study quantified the protein expression levels associated with inflammatory responses through a combination of immunohistochemical staining and western blotting analyses.

This research investigated the interaction between D. dasycarpus active components and target proteins, including PTPN14, using a BIACORE system. The screened active components were identified as alkaloids through mass spectrometry. The UPLC-Orbitrap-MS analysis revealed that alkaloids were the predominant constituents in the 60% EtOH extract of D. dasycarpus. Alkaloid components significantly reduced the arthritis index, foot swelling, and serum antibody levels of IgG1, IgG 2a, and IgG 2b in CIA mice. Histological staining results indicated that alkaloid components mitigate disease exacerbations in CIA mice. Bioinformatics analysis and protein level detection results show that the therapeutic mechanism of D. dasycarpus in managing RA could be attributed to the suppression of the IL-17 signaling pathway.

This study was based on clarifying the therapeutic effect of D. dasycarpus on RA, identifies its effective chemical components as alkaloids. It systematically elucidates the pharmacological mechanisms of alkaloids in treating RA, thereby laying a crucial theoretical foundation for further exploration of the active constituents of D. dasycarpus.

Interleukin (IL)-17, a pro-inflammatory cytokine, plays a pivotal role in immune regulation by bridging innate and adaptive responses. Beyond its canonical involvement in T helper-17 cells-mediated immunity, IL-17 contributes significantly to the pathogenesis of systemic autoinflammatory diseases (SAIDs) including Familial Mediterranean Fever (FMF), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-associated autoinflammatory diseases, and synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. Dysregulated IL-17 signaling drives inflammasome activation, neutrophil recruitment, and chronic tissue inflammation. IL-17 inhibitors have demonstrated efficacy in refractory SAIDs, though challenges such as increased infection risks, paradoxical inflammatory reactions, and uncertainties regarding long-term safety persist. Currently, there is insufficient data to support the use of IL-17 inhibitors as first-line treatments, and their role in managing SAIDs is yet to be fully defined. This review highlights the mechanistic role of IL-17 in SAIDs and emerging therapeutic strategies, including IL-17-targeted monotherapies and combination approaches with IL-1 or tumor necrosis factor (TNF) inhibitors. Future research should focus on biomarker development, combination therapies, and long-term studies to optimize the safety and efficacy of IL-17-targeted therapies in SAIDs.

The epithelial cell rests of Malassez (ERM) are located within the periodontal ligament. They are reportedly involved in maintaining homeostasis, particularly with regards to the thickness of the periodontal ligament. Their role in apical periodontitis lesions remains unclear, however. This study investigated the response of ERM to infection with Porphyromonas gingivalis. After being infected, the morphology of the P. gingivalis-infected cells was observed using confocal laser-scanning microscopy. The gene expression of P. gingivalis-infected and uninfected cells was investigated by RNA-sequencing analysis. Morphological observation showed the invasion and adhesion of P. gingivalis to the surface of ERM. The RNA analysis showed that the gene expression profile significantly differed between the infected and uninfected cells. At an expression level of ≥2 and false discovery rate of <0.1, the infected cells showed a decrease in 99 genes and an increase in 6 compared with in the non-infected cells. Most of the upregulated genes were unique to epithelial cells, such as endothelial cell-specific molecules and cytokeratin 5; the upregulated genes were associated with the immune response, however. These results indicate that ERM upregulate genes associated with epithelial cells and suppress those associated with the immune response following P. gingivalis infection.

Regulatory T (Treg) cells are a critical immune component guarding against excessive inflammation. Treg cell dysfunction can lead to chronic inflammatory diseases with current therapies aimed at inhibiting effector T cells rather than rescuing Treg cell function. We utilized single-cell RNAsequencing data from patients with chronic inflammation to identify SAT1, the gene encoding spermidine/spermine N1-acetyltransferase (SSAT), as a driver of skin-resident Treg cell dysfunction. CRISPRa-driven SAT1 expression in human skin-derived Treg cells impaired their suppressive function and induced a pro-inflammatory phenotype. During cutaneous type-17 inflammation, keratinocyte 4-1BBL induces SAT1 on Treg cells. In a mouse model of psoriasis, pharmacological inhibition of SSAT rescued Treg cell number and function. Together, these data show that SAT1 expression has severe functional consequences on Treg cells and suggest a therapeutic target to treat chronic inflammatory disease.

24-Nor-ursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid for treating immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC).

Since PSC strongly associates with T helper-type-like 17 (TH17)-mediated intestinal inflammation, we explored NorUDCA's immunomodulatory potential on TH17 cells.

NorUDCA's impact on TH17 differentiation was assessed using a CD4+TNaive adoptive transfer mouse model, and on intraepithelial TH17 pathogenicity and transdifferentiation using an αCD3 stimulation model combined with interleukin-17A-fate-mapping. Mechanistic studies used molecular and multiomics approaches, flow cytometry and metabolic assays with pathogenic (p) TH17. Pathogenicity of pTH17 exposed to NorUDCA in vitro was evaluated following adoptive transfer in intestinal tissues or the central nervous system (CNS). Key findings were validated in an αCD3-stimulated humanised NSG mouse model reconstituted with peripheral blood mononuclear cells from patients with PSC.

NorUDCA suppressed TH17 effector function and enriched regulatory T cell (Treg) abundance upon CD4+TNaive cell transfer. NorUDCA mitigated intraepithelial TH17 pathogenicity and decreased the generation of proinflammatory 'TH1-like-TH17' cells, and enhanced TH17 transdifferentiation into Treg and Tr1 (regulatory type 1) cells in the αCD3-model. In vivo ablation revealed that Treg induction is crucial for NorUDCA's anti-inflammatory effect on TH17 pathogenicity. Mechanistically, NorUDCA restrained pTH17 effector function and simultaneously promoted functional Treg formation in vitro, by attenuating a glutamine-mTORC1-glycolysis signalling axis. Exposure of pTH17 to NorUDCA dampened their pathogenicity and expansion in the intestine or CNS upon transfer. NorUDCA's impact on TH17 inflammation was corroborated in the humanised NSG mouse model.

NorUDCA restricts TH17 inflammation in multiple mouse models, potentiating future clinical applications for treating TH17-mediated intestinal diseases and beyond.

Primary sclerosing cholangitis (PSC) is a rare immune-mediated hepatobiliary disease, characterised by progressive biliary fibrosis, cirrhosis, and end-stage liver disease. As yet, no licensed pharmacological therapy exists. While significant advancements have been made in our understanding of the pathophysiology, the exact aetiology remains poorly defined. Compelling evidence from basic science and translational studies implicates the role of T helper 17 cells (Th17) and the interleukin 17 (IL-17) pro-inflammatory signalling pathway in the pathogenesis of PSC. However, exploration of the safety and efficacy of inhibiting the IL-17 pathway in PSC is lacking.

This is a phase 2a, open-label, multicentre pilot study, testing the safety of brodalumab, a recombinant human monoclonal antibody that binds with high affinity to interleukin-17RA, in adults with PSC. This study will enrol 20 PSC patients across five large National Health Service tertiary centres in the UK. The primary outcome of the study relates to determining the safety and feasibility of administering brodalumab in early, non-cirrhotic PSC patients. Secondary efficacy outcomes include non-invasive assessment of liver fibrosis, changes in alkaline phosphatase values and other liver biochemical readouts, assessment of biliary metrics through quantitative MR cholangiography+, and quality of life evaluation on completion of follow-up (using the 5D-itch tool, the PSC-patient-reported outcome and PSC-specific Chronic Liver Disease Questionnaire).

Ethical approval for this study has been obtained from the London Bridge Research Ethics Committee (REC23/LO/0718). Written informed consent will be obtained from all trial participants prior to undertaking any trial-specific examinations or investigations. On completion of the study, results will be submitted for publication in peer-reviewed journals and presented at national and international hepatology meetings. A summary of the findings will also be shared with participants and PSC communities.

ISRCTN15271834.

In the initial stage of the COVID-19 pandemic, high case fatality was noted. The case fatality during this was associated with the cytokine storm (CS) or cytokine storm syndrome (CSS). Sometimes, virus infections are due to the excessive secretion of pro-inflammatory cytokines, leading to cytokine storms, which might be directed to ARDS, multi-organ failure, and death. However, it was noted that several miRNAs are involved in regulating cytokines during SARS-CoV-2 and other viruses such as IFNs, ILs, GM-CSF, TNF, etc. The article spotlighted several miRNAs involved in regulating cytokines associated with the cytokine storm caused by SARS-CoV-2 and other viruses (influenza virus, MERS-CoV, SARS-CoV, dengue virus). Targeting those miRNAs might help in the discovery of novel therapeutics, considering CS or CSS associated with different virus infections.

The impaired immune regulation of bone marrow mesenchymal stem cells (BM-MSCs) disrupts T-cell homeostasis and alters the immunological environment in individuals with systemic lupus erythematosus (SLE). However, the specific molecular mechanisms underlying the defective immune functions of BM-MSCs in patients with SLE remain unclear. Here, we report that BM-MSCs derived from MRL/lpr mice exhibit a diminished proliferative capacity, elevated levels of aryl hydrocarbon receptor (AhR) and increased levels of secreted proinflammatory cytokines, including IL-1β, IL-6, and TNF-α. These BM-MSCs can increase splenocyte proliferation and upregulate the expression of retinoic acid receptor-related orphan receptor gamma t (RORγt) in EL4 cells, which constitute a murine T-cell lymphoblastic leukemia cell line. Furthermore, MRL/lpr mice treated with FICZ (an AhR agonist) displayed splenomegaly and exacerbated renal pathology, alongside increased levels of AhR, and inflammatory cytokines. Notably, BM-MSCs isolated from FICZ-treated mice also facilitated splenocyte proliferation and increased the RORγt level in EL4 cells during coculture. Similar effects were observed when BM-MSCs were exposed to FICZ in vitro, but these effects were reversed by the administration of CH223191 (an AhR antagonist). Additionally, the expression of Yes-associated protein (YAP) was significantly increased in both MRL/lpr mice and FICZ-treated BM-MSCs. Importantly, verteporfin (a Hippo-YAP inhibitor) attenuated the elevated RORγt levels in EL4 cells and the increased splenocyte proliferation. This study advances our understanding of SLE pathogenesis by pinpointing AhR as a pivotal modulator of the inflammatory response of BM-MSCs through the Hippo-YAP pathway in individuals with SLE. This novel insight not only enriches the current knowledge of SLE mechanisms but also highlights new potential therapeutic targets for SLE.

ZEB1, a zinc-finger E homeobox-binding transcription factor most frequently associated with developmental programs linked to epithelial-mesenchymal transition, has been demonstrated to regulate immune cell function. The study aimed to investigate the expression pattern of ZEB1 in Th17 cells and its colocalization with p-STAT3 in human apical periodontitis lesions.

Thirty-nine human periapical tissues were collected for ex vivo study, including periapical granulomas (PGs, n = 14), radicular cysts (RCs, n = 12), and healthy control tissues (control group, n = 13). Inflammatory infiltration of the lesions was assessed using hematoxylin-eosin staining. The expression of ZEB1 was detected and analyzed by immunohistochemistry. The localization of ZEB1 in Th17 cells and its colocalization with p-STAT3 were assessed using fluorescence colocalization.

ZEB1 expression was significantly higher in PGs and RCs than in the healthy control group; however no significant difference between the two groups was observed. Immunofluorescence analysis revealed that ZEB1 expression was correlated with IL17 and CD4 double-positive cells in human periapical lesions. ZEB1/ p-STAT3 double-positive cells were predominant in RCs and PGs than in the healthy control group.

The expression of ZEB1 was significantly elevated in PGs and RCs, and correlated with Th17 cells and p-STAT3 expression. This study revealed that ZEB1 is a potential player correlated with STAT3 activation and Th17 cells in apical periodontitis pathogenesis.

The oral microbiome comprises over 700 distinct species, forming complex biofilms essential for maintaining oral and systemic health. When the microbial homeostasis in the periodontium is disrupted, pathogens within the biofilm can cause periodontitis and peri-implantitis, inducing host immune responses. Understanding the role of microbial communities and the immune mechanisms in oral health and disease is crucial for developing improved preventive, diagnostic and therapeutic strategies. However, many questions remain about how changes in bacterial populations contribute to the development and progression of these conditions. An electronic and manual literature search was conducted using PubMed, Excerpta Medica, Frontiers Reports and the Wiley Online Library databases for relevant articles. Data from these publications were extracted and the overall findings were summarized in a narrative manner. The variations in microbial communities and immune responses of periodontitis and peri-implantitis are explored. Dysbiosis of the subgingival microbiome-characterized by an increase in pathogenic bacteria such as Porphyromonas gingivalis, Tannerella forsythia, and Aggregatibacter actinomycetemcomitans-plays a pivotal role in the initiation and progression of periodontitis. As for peri-implantitis, alterations include a higher abundance of opportunistic pathogens and reduced microbial diversity around implants. Moreover, oral dysbiosis potentially influencing systemic health through immune-mediated pathways. Regional immunity of periodontium involving neutrophils, T helper cells-17, and immune-related cytokines is crucial for maintaining periodontal homeostasis and responding to microbial imbalances. Additionally, the impact of non-mechanical treatments-such as probiotics and laser therapy-on the oral microbiome is discussed, demonstrating their potential in managing microbial dysbiosis. These findings underscore that bacterial dysbiosis is a central factor in the development of periodontitis and peri-implantitis. Maintaining microbial balance is essential for preventing these diseases, and interventions targeting the microbiome could enhance treatment outcomes. Strategies focusing on controlling pathogenic bacteria, modulating immune responses, and promoting tissue regeneration are key to restoring periodontal stability. Further research is needed to clarify the mechanisms underlying the transition from peri-implant mucositis to peri-implantitis and to optimize prevention and treatment approaches, considering the complex interactions between the microbiome and host immunity.

Asthma experienced by both adults and children is a phenotypically heterogeneous condition. Severe asthma, characterized by ongoing symptoms and airway inflammation despite high doses of inhaled and/or systemic corticosteroids, is the focus of research efforts to understand this underlying heterogeneity. Clinical phenotypes in both adult and pediatric asthma have been determined using supervised definition-driven classification and unsupervised data-driven clustering methods. Efforts to understand the underlying inflammatory patterns of severe asthma have led to the seminal discovery of type 2-high versus type 2-low phenotypes and to the development of biologics targeted at type 2-high inflammation to reduce the rates of severe asthma exacerbations. Type 2-high asthma is characterized by upregulation of T helper 2 immune pathways including interleukin (IL)-4, IL-5, and IL-13 along with eosinophilic airway inflammation, sometimes allergic sensitization, and responsiveness to treatment with corticosteroids. Type 2-low asthma is poorly responsive to corticosteroids and is not as well characterized as type 2-high asthma. Type 2-low asthma is limited by being defined as the absence of type 2-high inflammatory markers. Choosing a biologic for the treatment of severe asthma involves the evaluation of a panel of biomarkers such as blood eosinophils, total and specific immunoglobulin E/allergic sensitization, and fractional exhaled nitric oxide. In this review, we focus on the underlying pathobiology of adult and pediatric asthma, discuss the different phenotype-based treatment options for adult and pediatric type 2-high with or without allergic asthma and type 2-low asthma, and describe a clinical phenotyping approach to patients to guide out-patient therapy. Finally, we end with a discussion of whether pediatric asthma exacerbations necessitating admission to an ICU constitute their own high-risk phenotype and/or whether it is a part of other previously defined high-risk subgroups such as difficult-to-control asthma, exacerbation-prone asthma, and severe treatment-resistant asthma.

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology. This study aims to explore the potential mechanisms by which solute carrier family 7 member 11 (SLC7A11) influences RA development.

Collagen-induced arthritis (CIA) mice were constructed to observe disease onset and pathological scores. Pathological changes were examined using Hematoxylin-eosin and Safranin O-Fast Green staining. Levels of lactate dehydrogenase (LDH), inflammatory cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-18 and IL-1β), and oxidative stress (reactive oxygen species, malondialdehyde, and glutathione) were measured using ELISA. Western blotting was performed to detect the expression of pyroptosis- and pathway-related proteins. Fibroblast-like synoviocytes of RA (RA-FLS) were treated with TNF-α. Cell migration, invasion, and Caspase-1 levels were assessed through scratch assays, Transwell assays, and flow cytometry, respectively. The correlation between SLC7A11 and immune cell infiltration in RA was analyzed using bioinformatics. Additionally, downstream pathways of SLC7A11 in RA were screened, and the impacts of SLC7A11 on these pathways were validated in vitro.

CIA mice were successfully established, revealing significant downregulation of SLC7A11 in RA. Staining results indicated that overexpression of SLC7A11 significantly mitigated joint damage in CIA mice. In vitro experiments demonstrated that overexpression of SLC7A11 inhibited migration, invasion, and Caspase-1 expression levels in TNF-α-induced RA-FLSs. Furthermore, SLC7A11 suppressed inflammation, LDH release, and oxidative stress, while inhibiting pyroptosis. SLC7A11 expression was significantly different in multiple immune cells. The IL-17 pathway was identified as a downstream pathway of SLC7A11, and SLC7A11 inhibited the expression of IL-17 pathway proteins. Additionally, rhIL-17A, an activator of the IL-17 pathway, attenuated the inhibitory effects of SLC7A11 on inflammation, oxidative stress, and pyroptosis.

SLC7A11 suppresses pyroptosis to alleviate RA development by inhibiting the IL-17 pathway.

Uveitis refers to a diverse group of inflammatory diseases that affecting the uveal tract, comprising the iris, ciliary body, and choroid, with potential repercussions ranging from visual impairment to blindness. The role of autoimmunity in uveitis etiology is complex and still under investigation. CD4+ T cells intricately regulate immune responses in uveitis through their diverse subtypes: Th1, Th2, Th17, Treg (T regulatory), and Tfh (follicular T helper) cells. Each T cell subtype secretes specific cytokines with either pathogenic or protective implications in uveitis. Th1 cells, characterized by IFN-γ secretion and T-bet expression, drive type 1 immune responses against intracellular pathogens. Conversely, Th2 cells, which produce interleukin (IL)-4, IL-5, and IL-13 and express the transcription factor GATA3, mediate type 2 immune responses to larger extracellular threats like helminths. Th17 cells, generating IL-17 and IL-22 and controlled by RORγt, engage in type 3 immune responses against select pathogens. Tfh cells, releasing IL-21 and governed by Bcl6, aid B cell antibody production. Conversely, Tregs, identified by Foxp3, exert regulatory functions in immune homeostasis. This review delves into the roles of CD4+ T cell-derived cytokines in uveitis, emphasizing their intricate involvement in disease progression and resolution. Insight into these mechanisms might guide therapeutic approaches targeting CD4+ T cell responses in uveitis management.

Melatonin (MLT) can improve mitophagy, thereby ameliorating cognitive deficits in Alzheimer's disease (AD) patients. Hence, our research focused on the potential value of MLT-related genes (MRGs) in AD through bioinformatic analysis.

First, the key cells in the single-cell dataset GSE138852 were screened out based on the proportion of annotated cells and Fisher's test between the AD and control groups. The differentially expressed genes (DEGs) in the key cell and GSE5281 datasets were identified, and the MRGs in GSE5281 were selected via weighted gene coexpression network analysis. After intersecting two sets of DEGs and MRGs, we performed Mendelian randomization analysis to identify the MRGs causally related to AD. Biomarkers were further ascertained through receiver operating characteristic curve (ROC) and expression analysis in GSE5281 and GSE48350. Furthermore, gene set enrichment analysis, immune infiltration analysis and correlation analysis with metabolic pathways were conducted, as well as construction of a regulator network and molecular docking.

According to the Fisher test, oligodendrocytes were regarded as key cells due to their excellent abundance in the GSE138852 dataset, in which there were 281 DEGs between the AD and control groups. After overlapping with 3,490 DEGs and 550 MRGs in GSE5281, four genes were found to be causally related to AD, namely, G protein-coupled receptor, family C, group 5, member B (GPRC5B), Methyltransferase-like protein 7 A (METTL7A), NF-κB inhibitor alpha (NFKBIA) and RAS association domain family 4(RASSF4). Moreover, GPRC5B, NFKBIA and RASSF4 were deemed biomarkers, except for METTL7A, because of their indistinctive expression between the AD and control groups. Biomarkers might be involved in oxidative phosphorylation, adipogenesis and heme metabolism. Moreover, T helper type 17 cells, natural killer cells and CD56dim natural killer cells were significantly correlated with biomarkers. Transcription factors (GATA2, POU2F2, NFKB1, etc.) can regulate the expression of biomarkers. Finally, we discovered that all biomarkers could bind to MLT with a strong binding energy.

Our study identified three novel biomarkers related to MLT for AD, namely, GPRC5B, NFKBIA and RASSF4, providing a novel approach for the investigation and treatment of AD patients.

Thymic epithelial tumors (TETs) are rare neoplasms typically located in the anterior mediastinum. While immune checkpoint inhibitors (ICIs) show promise for advanced or refractory TETs, their clinical application is hindered by heterogeneous responses across TET subtypes, lack of reliable predictive markers, and the risk of immune-related adverse events (irAEs).

We analyzed TCGA, GEO, and GTEx databases to identify differentially expressed genes (DEGs) among three TET subtypes. Comprehensive enrichment analysis determined gene functions and pathways. CIBERSORT analysis revealed subtype-specific immune infiltration profiles. We assessed immune-related genes using immune/stromal scores, TIDE scores, and immune checkpoint gene correlation analysis. Immunohistochemistry was performed to evaluate FGF17 and PD-L1 protein expression levels and their correlation in TET samples.

Our findings revealed distinctive molecular and immune infiltration patterns across TET subtypes. Pathway analysis showed upregulation of immune-related pathways in type C. CIBERSORT analysis revealed higher fractions of plasma cells and activated CD4 T cells in type C and increased resting dendritic cells in type A or B3. Furthermore, we identified 1,100 DEGs between responders and non-responders to pembrolizumab. FGF17 emerged as a potential predictive marker for immunotherapy response, showing significantly lower expression in type C and a strong negative correlation with PD-L1 expression (P < 0.001). We identified 115 genes potentially linked to irAEs, with CXCL8, IL17A, and CD40LG among the top hub genes in the protein-protein interaction network.

This study provides insights into subtype-specific molecular and immune characteristics of TETs, identifies FGF17 as a potential negative biomarker for immunotherapy response (with lower expression potentially indicating better response), and elucidates mechanisms of irAEs. These findings contribute to the development of targeted immunotherapeutic approaches for managing TETs, particularly in predicting response to immune checkpoint inhibitors.

Pulmonary fibrosis (PF) is a progressive, irreversible disease characterized by heterogeneous interstitial lung tissue damage. It originates from persistent or repeated lung epithelial injury and leads to the activation and differentiation of fibroblasts into myofibroblasts. Interleukins (ILs) are a group of lymphokines crucial for immunomodulation that are implicated in the pathogenesis of PF. However, different types of ILs exert disparate effects on PF. In the present review, based on the effect on PF, ILs are classified into three categories: i) Promotors of PF; ii) inhibitors of PF; and iii) those that exert dual effects on PF. Several types of ILs can promote PF by provoking inflammation, initiating proliferation and transdifferentiation of epithelial cells, exacerbating lung injury, while other ILs can inhibit PF through suppressing expression of inflammatory factors, modulating the Th1/Th2 balance and autophagy. The present review summarizes the association of ILs and PF, focusing on the roles and mechanisms of ILs underlying PF.

Recently, it has been realized that immune processes participate in the pathogenesis of human cancers. A large number of genetic polymorphisms in immune-related genes have been extensively examined for their roles in the susceptibility of gastric cancer (GC) and colorectal cancer (CRC), including IL4 gene rs2070874, IL4RA gene rs1801275, IL18 gene rs187238, IL18RAP gene rs917997, IL17A gene rs8193036, IL23R gene rs1884444 and IL23R gene rs10889677. However, there is no consistent conclusion, which calls for further research. In this case-control study, these 7 genetic polymorphisms were genotyped by Sanger sequencing in a total of 1247 patients with cancer (GC/CRC: 460/787) and 800 healthy individuals. A total of 31 previous studies and our present study were included in this meta-analysis. The case-control study revealed that in Hubei Chinese population, rs2070874, rs187238 and rs10889677 were significantly associated with CRC risk, whereas only rs917997 was significantly associated with GC risk. The meta-analysis showed that rs2070874, rs917997, rs8193036 and rs1884444 were significantly associated with GC risk in Chinese population, whereas rs2070874 in total population, rs1801275 in Asian population and rs187238 in Chinese population were significantly associated with CRC risk. IL4 gene rs2070874, IL18RAP gene rs917997, IL17A gene rs8193036 and IL23R gene rs1884444 may serve as the susceptible factors for GC carcinogenesis in Chinese population. IL4 gene rs2070874 in total population, IL4RA gene rs1801275 in Asian population and IL18 gene rs187238 in Chinese population may be genetic biomarkers for CRC susceptibility.

Atherosclerosis, the leading cause of death worldwide, is a chronic inflammatory disease leading to the accumulation of lipid-rich plaques in the intima of large and medium-sized arteries. Accumulating evidence indicates the important regulatory role of the adaptive immune system in atherosclerosis during all stages of the disease. The gut microbiome has also become a key regulator of atherosclerosis and immunomodulation. Whilst existing research extensively explores the impact of the microbiome on the innate immune system, only a handful of studies have explored the regulatory capacity of the microbiome on the adaptive immune system to modulate atherogenesis. Building on these concepts and the pitfalls on the gut microbiota and adaptive immune response interaction, this review explores potential strategies to therapeutically target the microbiome, including the use of prebiotics and vaccinations, which could influence the adaptive immune response and consequently plaque composition and development.

Retinal detachment (RD) is a common acute blinding eye disease, and dexamethasone (DEX), an adrenocorticosteroid, shows protective effects against RD. However, its poor water solubility and low bioavailability limit its effectiveness. To address this, we developed SF@DEX nanomaterials and investigated their therapeutic potential and mechanisms in RD. The nanomaterials were successfully synthesized and characterized, achieving 90% encapsulation efficiency and releasing 60% of DEX within 12 h.In vitro, phagocytosis was measured by flow cytometry, and enzyme-linked immunosorbent assay determined interleukin-17 (IL-17) and interleukin-10 (IL-10) levels. A rat RD model was established surgically, followed by oral administration of silk fibroin (SF), SF@DEX, and DEX. Polymerase chain reaction (PCR) assessed IL-17A and forkhead box P3 (FOXP3) expression, while Western blot analysed transforming growth factor-β1 (TGF-β1), IL-10, IL-17A, and FOXP3 levels. Apoptosis of retinal ganglion cells was evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and confocal microscopy detected colocalization of IL-17A and FOXP3. SF@DEX treatment significantly reduced Th17 cells and IL-17A while increasing Tregs, FOXP3, TGF-β1, and IL-10 levels. The severity of RD in rats was notably alleviated by SF@DEX, demonstrating its anti-inflammatory effects through modulation of the Th17/Treg immune balance. These results highlight SF@DEX as a promising nano-based therapy for RD.

Septic arthritis (SA) caused by Staphylococcus aureus is a severe inflammatory joint disease, characterized by synovitis accompanied with cartilage destruction and bone erosion. The available antibiotic treatment alone is insufficient to resolve the inflammation that leads to high rates of morbidity and mortality. Among the CD4+ T helper lymphocytes, the Th17 and Tregs are key regulators of immune homeostasis. A high Th17 could lead to autoimmunity, whereas an increase in Tregs indicates immunosuppression. Depending on the external cytokine milieu, naïve CD4+ T cells transform into either Th17 or Treg cell lineage. TGF-β in the presence of IL-21 produces Th17 cells and drives the inflammatory cascade of reactions. We studied the effects of in vivo neutralization of TGF-β and IL-21 in septic arthritic mice to control arthritic inflammation, which has not been studied before. The arthritic index showed maximum severity in the SA group which substantially reduced in the Ab-treated groups. Flow cytometric analyses of peripheral blood collected from mice at 9DPI revealed the highest Th17/Treg ratio in the SA group but least in the combined-antibody-treated group. TGF-β1 and IL-21 cytokine production from serum, spleen, and synovial tissue homogenates was significantly reduced in the dual Ab-treated group than in the untreated SA group. From the Western blot analyses obtained from splenic lymphocytes at 9 DPI, we elucidated the possible underlying mechanism of interplay in downstream signalling involving the interaction between different STAT proteins and SOCS, NF-κB, RANKL, mTOR, iNOS, and COX-2 in regulating inflammation and osteoclastogenesis. On endogenous blockade with TGF-β and IL-21, the Th17/Treg ratio and resultant arthritic inflammation in SA were found to be reduced. Therefore, maintaining the Th17/Treg balance is critical to eradicate infection as well as suppress excessive inflammation and neutralization of TGF-β and IL-21 could provide a novel therapeutic strategy to treat staphylococcal SA.

Structural, functional, and molecular-level changes in the aging heart are influenced by a dynamic interplay between immune signaling and cellular metabolism that is referred to as immunometabolism. This review explores the crosstalk between cellular metabolic pathways including glycolysis, oxidative phosphorylation, fatty acid metabolism, and the immune processes that govern cardiac aging. With a rapidly aging population that coincides with increased cardiovascular risk and cancer incidence rates, understanding the immunometabolic underpinnings of cardiac aging provides a foundation for identifying therapeutic targets to mitigate cardiac dysfunction. Aging alters the immune environment of the heart by concomitantly driving the changes in immune cell metabolism, mitochondrial dysfunction, and redox signaling. Shifts in these metabolic pathways exacerbate inflammation and impair tissue repair, creating a vicious cycle that accelerates cardiac functional decline. Treatment with cancer therapy further complicates this landscape, as aging-associated immunometabolic disruptions augment the susceptibility to cardiotoxicity. The current review highlights therapeutic strategies that target the immunometabolic axis to alleviate cardiac aging pathologies. Interventions include modulating metabolic intermediates, improving mitochondrial function, and leveraging immune signaling pathways to restore cardiac health. Advances in immunometabolism thus hold significant potential for translating preclinical findings into therapies that improve the quality of life for the aging population and underscore the need for approaches that address the immunometabolic mechanisms of cardiac aging, providing a framework for future research.