Viral encephalitis (VE), is a life-threatening neurological disorder marked by inflammation of brain parenchyma, driven by direct viral cytotoxicity and host immune-mediated injury. Globally, its incidence ranges from 1.4 to 13.8 cases per 100,000 individuals annually, with significant morbidity and mortality in endemic regions such as India, among children. Neurotropic viruses including herpes simplex virus (HSV), Japanese encephalitis virus (JEV) and West Nile virus, enter central nervous system via hematogenous or neuronal routes, triggering viral replication, cytokine release and blood-brain barrier disruption, resulting in seizures, cerebral edema and long-term neurological deficits. Current management in neurological intensive care relies on immunity-oriented strategies: Acyclovir as first-line antiviral for HSV and varicella-zoster virus, antiepileptics to control seizures and limit secondary neuronal injury and corticosteroids to modulate harmful neuroinflammation and cerebral edema. Emerging therapies, including novel antivirals (favipiravir, remdesivir, brincidofovir), monoclonal antibodies, cytokine inhibitors (tocilizumab, anakinra) and B-cell/plasma cell-targeted agents (rituximab, daratumumab), offer promise by simultaneously addressing viral replication and immune dysregulation. Personalized biomarker-guided integrating pathogen-directed and host-targeted therapies may optimize outcomes, reduce neuronal injury and improve recovery. This review underscores the importance of a multidimensional, immunity-oriented treatment paradigm, highlighting both established and emerging strategies to enhance prognosis and long-term neurological functions in patients with viral encephalitis.

A 3-year-old boy with speech delay presented with fever and choreoathetosis, progressing to cardiogenic shock and respiratory failure. He met diagnostic criteria for multisystem inflammatory syndrome in children (MIS-C) and improved with treatment, which included intravenous immune globulin (IVIG), methylprednisolone, and anakinra per hospital protocol. Following sedation weaning, choreoathetosis recurred. Repeat brain MRI revealed new symmetric T2 hyperintensity and restricted diffusion in the globi pallidi. He was discharged with persistent developmental regression, hypotonia, and choreoathetosis. Four months later, he was readmitted with respiratory failure from a human metapneumovirus infection and died from refractory cardiogenic shock and multiorgan failure. Posthumous exome sequencing identified a homozygous variant of unknown significance in MDH2 (malate dehydrogenase 2). A sibling with chronic encephalopathy and myocarditis shared this genotype. MDH2 deficiency is associated with movement disorders and cardiomyopathy. MIS-C plausibly triggered clinical decompensation in our patient. Genetic or metabolic causes should be considered in children with a history of developmental delay, acute neurologic symptoms, and symmetric basal ganglia lesions.

Two anatomically and functionally distinct populations of periodontium-derived fibroblasts can be identified: gingiva fibroblasts (GFs), which originate from the soft connective tissue of the gingiva and support epithelial attachment and tissue integrity, and periodontal ligament fibroblasts (PDLFs), which produce collagenous fibers that anchor teeth within the alveolar bone socket. Both cell types can contribute to osteogenesis when cultured in the presence of mineralization medium, and both cell types can drive osteoclast formation when co-cultured with osteoclast precursors. Under inflammatory conditions such as periodontitis, this balance is disturbed, leading to more osteoclast-driven bone resorption. The model system of osteogenesis and osteoclastogenesis can be used to further dissect the contributing factors of periodontitis by incorporating bacteria or their components like TLR agonists. Chronic inflammation can further be mimicked by using inflammatory cytokines such as IL-1β, TNF-α and Activin-A. Furthermore, bone anabolic and (anti-)catabolic medications such as parathyroid hormone (PTH), anti-TGF-β, sclerostin and anti-sclerostin can be used to investigate their effects on both osteogenesis and osteoclastogenesis. This platform is ideal for studying the effect of medication used in comorbidities of periodontitis, such as rheumatoid arthritis (RA; e.g., anakinra, infliximab) and diabetes (e.g., metformin), which have all been shown to inhibit osteoclast formation. The osteogenesis culture system can be manipulated over time, making it an ideal system for studying how the osteogenic stage of periodontium-derived fibroblasts affects subsequent osteoclast formation. Finally, fibroblast-based three-dimensional (3D) culture systems provide physiologically relevant environments that capture spatial cell-matrix interactions essential for hard and soft tissue repair in periodontal tissue regeneration. Collectively, these models help bridge in vitro findings toward optimized regenerative strategies.

Inflammation-driven tumor implantation, such as port-site metastasis (PSM) following laparoscopic gynecologic surgery and peritoneal seeding during post-surgical recurrence, represents an aggressive clinical problem that remains poorly understood and lacks targeted therapies. To address this, we developed a non-surgical Mesothelium-Inflammation/Injury-Metastasis (MIM) model and investigated the role of the IL-1β/IL1R1/MYD88/IRAK1/4 axis and NLRP3 in epithelial ovarian cancer (EOC) seeding at inflamed or injured sites. This model created by a needle injury recapitulates inflammation-driven peritoneal seeding and mimics PSM and inflammation associated dissemination in peritoneum during recurrence. Seeding was dependent on Il1r1 but not Nlrp3, despite its role in regulating IL-1β production, as Il1ra⁻/⁻ and Nlrp3⁻/⁻ mice phenocopied wild-type C57BL/6 mice. Given the limited antitumor efficacy of IL-1β-targeting agents such as Anakinra and Canakinumab, we focused on IRAK4 as a therapeutic target. IRAK4 knockdown significantly prolonged survival, reduced tumor cell adhesion, downregulated E-cadherin and Wnt4, and induced S-phase/mitotic arrest. This led to the development of UR241-2, a small-molecule IRAK4 inhibitor, which was validated through molecular simulations, hotspot analysis, nanoBRET, global kinome profiling, and NF-κβ reporter assays. UR241-2 inhibited NF-κβ nuclear translocation and blocked IL-1β-induced IRAK4 phosphorylation. UR241-2 exhibited favorable drug-like properties, including absence of CYP or hERG inhibition, and acceptable CaCo-2 permeability, plasma protein binding, microsomal stability, and pharmacokinetics. In vivo, UR241-2 reduced SKOV3 xenograft growth, suppressed mesothelial seeding, and increased MHC-II⁺ macrophages and activated neutrophils in syngeneic high-grade epithelial ovarian HGS3 tumors. RNA-seq revealed enrichment of neutrophil activation signatures and suppression of extracellular matrix (ECM) gene programs. Together, these findings establish a role for the IL-1β/IL1R1/IRAK4 axis in inflammation-driven PSM and peritoneal seeding and ECM regulation in EOC, and demonstrate that IRAK4 inhibition activates antitumor immune responses, providing a therapeutic strategy to block metastatic seeding and improve tumor control.

Post-traumatic osteoarthritis (OA) is driven by a sustained inflammatory response and progressive osteochondral damage. We compared the effects of a single intra-articular injection of anakinra (Interleukin-1 receptor antagonist; IL-1Ra) with those of betamethasone on structural cartilage outcomes and Interleukin-8 (IL-8) immunopositivity in a rabbit model of post-traumatic knee OA, and assessed the cytotoxicity of anakinra in primary human OA chondrocytes. Fifteen male New Zealand White rabbits underwent bilateral anterior cruciate ligament transection and partial medial meniscectomy and were randomized to receive saline (OA, control), betamethasone (0.5 mg/kg), or anakinra (0.6 mg/kg) at 2 weeks post-surgery (n = 5 rabbits/group; 10 knees/group, clustered within rabbit). At 14 weeks, cartilage damage was graded using the Osteoarthritis Research Society International (OARSI) cartilage OA pathology assessment system, and IL-8 immunopositivity in cartilage was quantified by immunohistochemistry. In vitro, chondrocytes from seven donors (Passages 0-1) were treated with anakinra (1 µM to 1 mM) for 24 h, and cell viability was evaluated by MTT and neutral red uptake (NRU) assays. Both anakinra and betamethasone shifted the OARSI grade distribution toward lower grades compared with OA (p < 0.001), with no difference between the treatments (p = 0.639). IL-8 immunopositivity was lower with both treatments and was lowest in the anakinra group (OA: 93.09 ± 6.1%; betamethasone: 22.93 ± 3.4%; anakinra: 9.58 ± 3.9%) (p < 0.01 OA vs. betamethasone; p < 0.001 OA vs. anakinra). Anakinra did not reduce chondrocyte viability at concentrations up to 500 µM (p > 0.05), whereas 1 mM reduced viability by approximately 10% (p < 0.05). These findings suggest that a single-dose intra-articular anakinra injection modulates the histomorphological characteristics of damaged cartilage by preserving chondrocyte viability and inhibiting IL-8 expression in post-traumatic knee OA.

We report a child with massive, chronic idiopathic pericardial effusion (PE), initially detected incidentally and asymptomatically. Despite multiple treatment attempts, including Nonsteroidal anti-inflammatory drugs, corticosteroids, colchicine, and repeated pericardiocentesis, the effusion persisted and recurred. Advanced imaging revealed a stable but severe PE over the years, with no hemodynamic compromise. Cytokine analysis of the pericardial fluid showed markedly elevated interleukin (IL)-6 levels, suggesting an underlying inflammatory process despite the absence of classic clinical signs. Based on this finding, the patient was successfully treated with anakinra, an IL-1 receptor antagonist, resulting in sustained remission for 24 months. This case highlights the potential role of biologic therapy in selected pediatric patients with chronic idiopathic PE, even when traditional markers of inflammation are absent. Cytokine profiling may help identify candidates for anti-IL-1 treatment, providing a valuable therapeutic option where standard approaches fail.

Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disorder characterized by quotidian fevers, arthralgia, transient rash, and elevated inflammatory markers, often leading to diagnostic delay due to overlap with infectious, autoimmune, and malignant conditions. We present the case of a 60-year-old Latina woman who developed daily fevers, polyarthralgia, rash, and hypoxemic respiratory failure. Despite broad-spectrum antibiotics, her symptoms persisted, and extensive infectious and hematologic evaluations were unrevealing. A diagnosis of AOSD was established based on the Yamaguchi criteria and markedly elevated ferritin. The patient responded to corticosteroids but later developed macrophage activation syndrome (MAS), requiring anakinra in addition to high-dose steroids. This case highlights the diagnostic challenges of AOSD in older adults, the potential for atypical systemic manifestations such as pulmonary nodules and anasarca, and the importance of early cytokine-directed therapy to prevent life-threatening complications.