The clinical impact of performing transcatheter aortic valve replacement (TAVR) in patients with chronic inflammatory systemic diseases (CIDs) is not well reported. Hence, we designed this study to evaluate whether coexistence of CIDs in TAVR patients leads to worse clinical outcomes. We retrospectively studied TAVR patients at our institution between 11/21/2011 and 03/29/2024. Patients diagnosed with chronic inflammatory diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma, Sjögren's syndrome, inflammatory bowel disease, or other related diseases were identified using International Classification of Diseases codes. Clinical outcomes during inpatient and at one-year were compared between CIDs and no-CID patients. Our study included 2,880 TAVR patients with mean age of 79±9 years, 45% were female, and 78% were Caucasian. CIDs patients comprised 6.4% (n=185) of the total cohort. The CIDs cohort had a higher proportion of females (61.6 vs. 43.9%, p<0.001), immunosuppressive therapy (5.9 vs. 2.9%, p=0.02), NYHA class III or IV symptoms (51.9 vs. 40%, p=0.04), and higher STS score (4.1 vs. 3.4; p=0.04). In-hospital mortality (0.0 vs. 1.7%; p=0.08) was similar between the CIDs and no-CIDs groups; however, vascular complications (10.3% vs 6.1%, p=0.036) and unplanned vascular interventions (5.4 vs. 1.9%; p=0.003) were more common in CIDs patients. Survival analysis showed no difference in one-year mortality (8.9 vs. 8.91%, log-rank p=0.73) between the two groups. In conclusion, TAVR in CIDs patients is safe and has comparable immediate and one-year adverse outcomes compared to non-CIDs patients, however these patients are more prone to vascular access complications and may require more unplanned vascular interventions.

Stress-induced upregulation of interleukin-6 (IL-6) signaling and its downstream pathophysiological consequences have garnered considerable attention in recent years. However, no comprehensive review has specifically examined the association between stress-induced IL-6 and its implications for bone health in children. During childhood, linear growth and peak bone mass acquisition are tightly regulated processes. Hence, this review aims to investigate current evidence on stress-induced IL-6 upregulation and its detrimental effects on pediatric bone health. Findings from animal models, knockout studies, pediatric inflammatory disorders, including juvenile idiopathic arthritis, pediatric systemic lupus erythematosus and inflammatory bowel disease, and models of metabolic stress collectively demonstrate that stress triggers IL-6, thereby impairing skeletal growth and increasing fragility. Data shows that persistent IL-6 upregulation not only disrupts the normal functioning of growth hormone, insulin-like growth factor-1 (GH/IGF-1) axis, enhances receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclastogenesis, and promotes bone marrow adiposity. Further, stress-induced high levels of IL-6 adversely affect the skeletal, immune, and endocrine systems, thereby compromising skeletal development and bone growth in children. Elevated systemic or local IL-6 levels may exert direct deleterious effects on bone by impairing stem cell differentiation and inhibiting the proliferation and maturation of growth plate chondrocytes, ultimately restricting longitudinal bone growth. Moreover, elevated IL-6 levels may also impair muscle health and crosstalk between muscle and bone, thereby compromising skeletal integrity. Collectively, these findings underscore the need for integrative therapeutic strategies that target inflammation and redox imbalance in bone and other tissues, particularly in children. Better understanding stress-induced IL-6 dysregulation is critical for pediatric bone development and long-term skeletal health.

Hypoxia-inducible factor-1α (HIF-1α) is a central regulator of cellular responses to hypoxia and plays a pivotal role in immune cell activation and functional reprogramming. This review summarizes how HIF-1α modulates inflammatory responses through metabolic regulation and examines its mechanistic involvement in autoimmune diseases. Under normoxic conditions, HIF-1α is rapidly degraded, whereas hypoxia, inflammation, or metabolic stress stabilizes the protein, allowing its nuclear translocation and activation of glycolysis-related genes. This shift drives immune cells from oxidative metabolism to glycolysis, supporting rapid energy production and promoting inflammation-associated functional states. Consequently, HIF-1α enhances the production of inflammatory mediators and forms positive feedback loops with inflammatory signaling pathways, influencing immune cell migration, survival, and function. Aberrant activation of HIF-1α is closely associated with disease activity in autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis, contributing to immune imbalance and tissue damage. However, its effects are context-dependent; in conditions like inflammatory bowel disease and uveitis, moderate activation may exert protective roles. Therefore, therapeutic strategies require precise, context-specific modulation rather than simple inhibition or activation. Although current drug development targeting HIF-1α focuses mainly on oncology, emerging approaches-including small molecule inhibitors, nanodelivery systems, and gene therapy-highlight its potential in autoimmune disease treatment. Overall, HIF-1α serves as a key link between hypoxia, metabolism, and immune regulation.

Immune cells play a central role in the pathogenesis and progression of autoimmune diseases. Recent evidence indicates that metabolites produced by the gut microbiota are essential for maintaining immune cell homeostasis. Indole-3-carboxaldehyde (IAld), a key gut microbial metabolite, has garnered considerable attention due to its immunomodulatory properties in autoimmune diseases. In multiple sclerosis, IAld alleviates inflammation through modulation of mast cells and astrocytes; in rheumatoid arthritis (RA), IAld suppresses macrophage-mediated inflammation while concurrently promoting angiogenesis and osteoclastogenesis; in inflammatory bowel disease (IBD), IAld confers protection through reducing inflammatory responses, promoting intestinal barrier repair, and modulating the gut microbiota composition. IAld mediates its immunomodulatory effects by directly or indirectly modulating immune cell function, including secretion and regulatory activity (including neutrophils, macrophages, innate lymphoid cells, T cells, and others) via the aryl hydrocarbon receptor (AhR) signaling pathway. In this review, we summarize the mechanisms by which IAld acts on immune cells and discuss its implications for autoimmune disease pathogenesis. Finally, we outline current challenges in this field and provide a perspective on future research priorities.

Pediatric inflammatory diseases, including juvenile idiopathic arthritis, pediatric inflammatory bowel disease, asthma, Kawasaki disease, and multisystem inflammatory syndrome in children, are an increasing global health concern. These conditions arise from dysregulated immune responses shaped by genetic susceptibility, environmental exposures, and the distinctive features of the developing pediatric immune system. This review presents a mechanism-centered overview of pediatric inflammation, emphasizing immune ontogeny, innate and adaptive immune dysregulation, cytokine signaling, inflammasome activation, oxidative stress, and the gut-immune axis. It also highlights emerging pathway-targeted therapies, including cytokine blockade, JAK inhibitors, microbiome-based interventions, and gene-editing strategies, with attention to their relevance for pediatric precision medicine. Early, mechanism-based intervention during critical developmental windows may improve long-term outcomes and reduce the lifetime burden of inflammatory disease. Overall, this review provides a concise, pediatric-focused perspective on how developmental immunology and targeted therapeutics can inform more precise and effective management of childhood inflammatory disorders.

The cytokine network is the central regulatory system for intercellular communication within the immune system. Its proper function depends on the dynamic balance between pro-inflammatory and anti-inflammatory cytokines. Through complex positive and negative feedback loops, this balance precisely regulates the intensity and duration of immune responses, thereby playing a critical role in both physiological and pathological states. This review systematically summarizes the compositional features and classification framework of the cytokine network, as well as the mechanisms by which it maintains homeostasis under physiological conditions. It further examines the manifestations of cytokine network imbalance in diseases such as sepsis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, and cancer. Available evidence suggests that these imbalances drive disease onset and progression primarily through cascade amplification of pro-inflammatory signaling, insufficient generation of anti-inflammatory signals, and aberrant epigenetic modification. These pathological changes are strongly influenced by factors such as infection, autoimmune dysregulation, and the tumor microenvironment (TME), together constituting the core pathological axis of "cytokine imbalance-immune dysregulation-disease progression." This review also summarizes current clinical strategies targeting the cytokine network, including monoclonal antibodies, Janus kinase (JAK) inhibitors, and emerging modalities such as bispecific antibodies and chimeric antigen receptor (CAR) cell therapy. In addition, it evaluates the clinical efficacy, potential risks, and future directions of these approaches. In summary, a deeper understanding of the binary balance within the cytokine network not only broadens our knowledge of immune regulation but also provides a theoretical basis and translational framework for the development of precision immune-targeted therapies.

The chemokine, CCL20, is the only ligand of CCR6 and acts as a molecular switch in immune homeostasis, affecting both protective immunity and pathological inflammation through spatiotemporal regulation of CCR6[+] leukocytes. CCL20 recruits Th17 cells, γδ T cells and ILC3s, forming synergistic antimicrobial networks with β-defensins and IgA to promote mucosal defense. Chronic CCL20 overexpression caused by NF-κB/MAPK signaling and epigenetic modification is responsible for self-perpetuating inflammation in rheumatoid arthritis, inflammatory bowel disease and psoriasis due to Th17-dominant feedback loops. CCL20 appears to have a role in organizing tertiary lymphoid structures and mediating gut-skin communication, which is affected by gut dysbiosis. Plasmonic nanoarrays and exosome profiling have enabled the discrimination of bioactive CCL20 isoforms with femtogram sensitivity, exposing the possibility for precision biomarker panels. Intelligent delivery systems, such as phase-responsive hydrogels and engineered probiotics, may enable tissue-specific therapeutic modulation. Challenges remain in the balancing of pathway inhibition with mucosal protection and trials of CCR6 antagonists have revealed risks of opportunistic infection. Future directions include dual-modality agents, AI-integrated multi-omics and circadian-timed interventions to preserve host defense during treatment for immunopathology.