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Inflammasomes, which mediate maturation of interleukin-1β (IL-β) and interleukin-18 (IL-18) and lead to pyroptosis, have been linked to various autoimmune disorders. This study investigated whether they are involved in the pathogenesis of autoimmune thyroiditis (AIT). We collected thyroid tissues from 50 patients with AIT and 50 sex- and age-matched controls. Serum levels of free T3, free T4, thyrotropin, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) were measured by electrochemiluminescent immunoassays. Expression of several inflammasome components, the NOD-like receptor (NLR) family pyrin domain containing 1 (NLRP1), NLRP3, CARD-domain containing 4 (NLRC4), absent in melanoma 2 (AIM2), the apoptosis-associated speck-like protein that contains a caspase recruitment domain (ASC), caspase-1, IL-1β, and IL-18 was determined by real-time PCR and western blot. Immunohistochemistry was used to localize the expression of NLRP1, NLRP3, NLRC4, and AIM2. The Nthy-ori 3-1 thyroid cell line was stimulated with tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-17A, interleukin-6, and poly(dA:dT). The levels of IL-18 and IL-1β in the cell supernatant were measured by enzyme-linked immunosorbent assay, and lactate dehydrogenase was quantified by absorptiometry. ASC specks were examined by confocal immunofluorescence microscopic analysis. Cell death was examined by flow cytometry, and the N-terminal domain of gasdermin D was detected by western blot analysis. Expression of NLRP1, NLRP3, NLRC4, AIM2, ASC, caspase-1, pro IL-1β, pro IL-18, mRNA, and protein was significantly increased in thyroid tissues from patients with AIT, and enhanced posttranslational maturation of caspase-1, IL-18 and IL-1β was also observed. Expression of NLRP1, NLRP3, NLRC4, and AIM2 was localized mainly in thyroid follicular cells adjacent to areas of lymphatic infiltration. The thyroid mRNA level of NLRP1 and ASC was correlated to the serum TPOAb and TgAb levels in the AIT group. TNF-α and IFN-γ had a priming effect on the expression of multiple inflammasome components in thyroid cells. IFN-γ was found to strengthen poly(dA:dT)-induced cell pyroptosis and bioactive IL-18 release. Our work has demonstrated for the first time that multiple inflammasomes are associated with AIT pathogenesis. The identified NLRP3, NLRP1, NLRC4, AIM2 inflammasomes and their downstream cytokines may represent potential therapeutic targets and biomarkers of AIT.

Porcine reproductive and respiratory syndrome virus (PRRSV) and classical swine fever virus (CSFV) are among the most economically devastating viral pathogens in the global swine industry, causing substantial and often incalculable economic losses. In field vaccination programs, the mutual interference between the immune responses elicited by CSFV and PRRSV vaccines markedly restricts the flexibility of immunization schedules, while the limited cross-protective capacity of current PRRSV vaccines remains an inherent and unavoidable challenge in swine disease management. To address these limitations, the present study aimed to develop a recombinant PRRSV-based live vector vaccine co-expressing two exogenous components: the protective E2 antigen of CSFV and porcine interleukin-18 (IL-18), with the objective of enhancing immunogenicity beyond that achievable with conventional monovalent formulations. Using a reverse genetics system derived from the attenuated PRRSV strain rHuN4-F112, the CSFV E2 gene was inserted between open reading frame 1b (ORF1b) and ORF2a, while a codon-optimized porcine IL-18 gene was integrated between ORF7 and the 3′ untranslated region. The resulting recombinant virus, designated rPRRSV-E2-N-IL18, was validated through dual restriction endonuclease digestion, plaque assays, indirect immunofluorescence assay, and Western blotting. Genetic stability was maintained for at least 25 serial passages, with persistent exogenous protein expression confirmed in the F25 generation. For immunogenicity assessment, fifteen PRRSV/CSFV double-negative piglets were randomly allocated into three groups: recombinant vaccine, parental virus, and unvaccinated control. Humoral and cellular immune responses were quantified by ELISA. During the 35-day post-vaccination period, no pyrexia associated with PRRSV infection was observed in the vaccine group, and histopathological examination of the lungs, lymph nodes, and kidneys showed no significant inflammatory lesions. Vaccinated pigs produced specific antibodies against both PRRSV and CSFV E2 within 35 days, and exhibited significantly elevated serum IL-18, IL-4, and IFN-γ levels, indicative of a potentiated Th1/Th2 response. These results confirm that IL-18 may indirectly enhance E2 immunogenicity by promoting Th1/Th2 responses, inducing robust humoral and cell-mediated immunity. This recombinant PRRSV platform represents a promising multivalent live vector vaccination strategy for the simultaneous prevention of PRRSV and CSFV in swine.

The inflammasome regulates the innate inflammatory response and is involved in autoimmune diseases. In this study, we explored the levels of IL-18 and IL-1β in serum and urine and the influence of various single-nucleotide polymorphisms (SNPs) on kidney lesions at diagnosis in patients with ANCA-associated vasculitis (AAV) and their clinical outcomes. Ninety-two patients with renal AAV were recruited, and blood and urine were collected at diagnosis. Serum and urine cytokine levels were measured by ELISA. DNA was extracted and genotyped using TaqMan assays for SNPs in several inflammasome genes. Lower serum IL-18 (p = 0.049) and the IL-18 rs187238 G-carrier genotype (p = 0.042) were associated with severe fibrosis. The IL-18 rs1946518 TT genotype was associated with an increased risk of relapse (p = 0.05), whereas GG was related to better renal outcomes (p = 0.031). The rs187238 GG genotype was identified as a risk factor for mortality within the first year after AAV diagnosis, independent of the requirement for dialysis or lung involvement (p = 0.013). We suggest that decreased cytokine levels could be a surrogate marker of scarring and chronicity of the renal lesions, together with the rs187238 GG genotype. If our results are validated, the rs1946518 TT genotype predicts the risk of relapse and renal outcomes during follow-up.

Interleukin-18 (IL-18), a pro-inflammatory cytokine belonging to the IL-1 Family, is a key mediator ofautoinflammatory diseases associated with the development of macrophage activation syndrome (MAS).High levels of IL-18 correlate with MAS and COVID-19 severity and mortality, particularly in COVID-19patients with MAS. As an inflammation inducer, IL-18 binds its receptor IL-1 Receptor 5 (IL-1R5), leadingto the recruitment of the co-receptor, IL-1 Receptor 7 (IL-1R7). This heterotrimeric complex subsequentlyinitiates downstream signaling, resulting in local and systemic inflammation. We reported earlier the development of a novel humanized monoclonal anti-human IL-1R7 antibody whichspecifically blocks the activity of human IL-18 and its inflammatory signaling in human cell and wholeblood cultures. In the current study, we further explored the strategy of blocking IL-1R7 inhyperinflammation in vivo using animal models. We first identified an anti-mouse IL-1R7 antibody that significantly suppressed mouse IL-18 andlipopolysaccharide (LPS)-induced IFNg production in mouse splenocyte and peritoneal cell cultures. Whenapplied in vivo, the antibody reduced Propionibacterium acnes and LPS-induced liver injury and protectedmice from tissue and systemic hyperinflammation. Importantly, anti-IL-1R7 significantly inhibited plasma,liver cell and spleen cell IFNg production. Also, anti-IL-1R7 downregulated plasma TNFa, IL-6, IL-1b,MIP-2 production and the production of the liver enzyme ALT. In parallel, anti-IL-1R7 suppressed LPSinducedinflammatory cell infiltration in lungs and inhibited the subsequent IFNg production andinflammation in mice when assessed using an acute lung injury model. Altogether, our data suggest that blocking IL-1R7 represents a potential therapeutic strategy to specificallymodulate IL-18-mediated hyperinflammation, warranting further investigation of its clinical application intreating IL-18-mediated diseases, including MAS and COVID-19.

Kupffer cells reside within the liver sinusoid and serve as gatekeepers. They produce pro- and anti-inflammatory cytokines and other biologically important molecules upon the engagement of pattern recognition receptors such as Toll-like receptors. Kupffer cell-ablated mice established by in vivo treatment with clodronate liposomes have revealed many important features of Kupffer cells. In this paper, we review the importance of Kupffer cells in murine acute liver injuries and focus on the following two models: lipopolysaccharide (LPS)-induced liver injury, which is induced by priming with Propionibacterium acnes and subsequent challenge with LPS, and hypercoagulability-mediated acute liver failure such as that in concanavalin A (Con A)-induced hepatitis. Kupffer cells are required for LPS sensitization induced by P. acnes and are a major cellular source of interleukin-18, which induces acute liver injury following LPS challenge. Kupffer cells contribute to Con A-induced acute liver failure by initiating pathogenic, intrasinusoidal thrombosis in collaboration with sinusoidal endothelial cells. The mechanisms underlying these models may shed light on human liver injuries induced by various etiologies such as viral infection and/or abnormal metabolism.

Background There is currently a lack of noninvasive biomarkers that effectively predict the progression of IgA nephropathy. We investigated the value of urinary IL-18 in predicting the progression of IgA nephropathy and whether its combination with clinical variables improved risk prediction. Methods A total of 136 patients with IgA nephropathy were followed up for a median of 36 months in four academic medical centers. The levels of three biomarkers, urinary IL-18, urinary KIM-1 and urinary NGAL, were measured via ELISA in patients with 136 IgA nephropathy. The progression of IgA nephropathy was defined as a > 50% decrease in the eGFR or end-stage kidney disease. Multivariate Cox regression analyses of urine biomarkers for predicting the progression of IgA nephropathy were performed, and the AUCs of the clinical prediction models were calculated. Results Kaplan–Meier analysis revealed that high levels (> 28.1 pg/mg of creatinine) of urinary IL-18 were associated with a significantly poor renal outcome ( P  < 0.01), and Cox analysis further confirmed this result. High levels of urinary IL-18 were associated with a 4.7-fold greater risk for IgA nephropathy progression in adjusted analyses. For predicting IgA nephropathy progression, urinary IL-18 yielded a C-statistic of 0.77 (95% CI, 0.67–0.86), renal injury molecule 1 yielded 0.75 (95% CI, 0.65–0.86), and uNGAL yielded 0.70 (95% CI, 0.59–0.80). Urinary IL-18 levels significantly improved the C statistic from 0.77 to 0.89, outperforming the clinical and MEST-C scores. Conclusion Urinary IL-18 is a significant predictor of poor renal outcomes and improves the risk prediction of IgA nephropathy.

The gastrointestinal epithelium is critical for maintaining a symbiotic relationship with commensal microbiota. Chronic morphine exposure can compromise the gut epithelial barrier in mice and lead to dysbiosis. Recently, studies have implicated morphine-induced dysbiosis in the mechanism of antinociceptive tolerance and reward, suggesting the presence of a gut-brain axis in the pharmacological effects of morphine. However, the mechanism(s) underlying morphine-induced changes in the gut microbiome remains unclear. The pro-inflammatory cytokine, Interleukin-18 (IL-18), released by enteric neurons can modulate gut barrier function. Therefore, in the present study we investigated the effect of morphine on IL-18 expression in the mouse ileum. We observed that chronic morphine exposure in vivo induces IL-18 expression in the ileum myenteric plexus that is attenuated by naloxone. Given that mu-opioid receptors (MORs) are mainly expressed in enteric neurons, we also characterized morphine effects on the excitability of cholinergic (excitatory) and vasoactive intestinal peptide (VIP)-expressing (inhibitory) myenteric neurons. We found fundamental differences in the electrical properties of cholinergic and VIP neurons such that VIP neurons are more excitable than cholinergic neurons. Furthermore, MORs were primarily expressed in cholinergic neurons, although a subset of VIP neurons also expressed MORs and responded to morphine in electrophysiology experiments. In conclusion, these data show that morphine increases IL-18 in ileum myenteric plexus neurons via activation of MORs in a subset of cholinergic and VIP neurons. Thus, understanding the neurochemistry and electrophysiology of MOR-expressing enteric neurons can help to delineate mechanisms by which morphine perturbs the gut barrier. Graphic Abstract

Background Signs and symptoms establish the diagnosis of adult onset Still’s disease (AOSD) as well as of systemic onset juvenile idiopathic arthritis (sJIA). The published data regarding the importance of IL-18 as a marker for diagnosis and disease activity so far are conflicting. The aim of this study was to clarify the role of IL-18 as a diagnostic and disease activity marker in AOSD and sJIA. Methods Thirty adult patients diagnosed with AOSD and twenty children diagnosed with sJIA were included in the study. Clinical and laboratory data were obtained retrospectively for each patient visit whenever IL-18 serum levels were determined. IL-18 levels were determined by ELISA. Sixty-five adults and twenty-three children presenting with fever and/or arthritis who did not meet the criteria for a diagnosis of AOSD or sJIA served as comparison groups. Rau’s criteria and CRP values were used to evaluate disease activity. Results IL-18 levels were significantly elevated in patients with active AOSD compared to AOSD patients in remission and to the comparison group with a median of 16,327 pg/ml, 470 pg/ml, and 368 pg/ml, respectively ( p  < 0.001). Analogous to AOSD in active sJIA, the median IL-18 serum level was significantly higher with 21,512 pg/ml than in the comparison group with 2580 pg/ml ( p  < 0.001). At our cut-off point of 5000 pg/ml, the calculated specificity of IL-18 to establish the diagnosis of AOSD was 96.9%, and the sensitivity 63.3% (AUC = 0.870, p < 0.001). For the diagnosis of sJIA, a cut-off value of 10,000 pg/ml was chosen with a specificity of 100% and a sensitivity of 60% (AUC = 0.774, p  = 0.003). At a cut-off value of 5000 pg/ml, the specificity was 62% and the sensitivity 65%. Conclusions This study gives further evidence to earlier publications of elevated IL-18 serum levels in active AOSD and sJIA, with up to 1000-fold higher concentrations compared to other rheumatic diseases. A clear association of IL-18 serum levels with disease activity in AOSD was found. The results support the use of IL-18 as an important biomarker in AOSD and sJIA.

Spinal cord injury (SCI) triggers a secondary injury cascade characterized by neuroinflammation, reactive gliosis, and neuronal apoptosis. While many pro-inflammatory cytokines contributing to this cascade reach peak upregulation within 24 h, Interleukin-18 (IL-18) exhibits a delayed upregulation profile, typically peaking 7 days post-injury. This review examines the temporal regulation and cell-specific roles contributing to the rise in IL-18 after SCI. Following primary insult, damage-associated molecular patterns prime and activate the NLRP3 inflammasome, which in turn drives latent IL-18 secretion. Cellularly, microglia function as the primary producers of IL-18 via the TLR4/p38-MAPK pathway, while astrocytes serve as the primary responders through IL-18R/p65-NF-κβ signaling. The microglia-astrocyte cross-talk propagates reactive gliosis, drives neuropathic pain, facilitates neuronal loss, and potentially contributes to the formation of the astrocytic border. Targeted therapeutic interventions such as upstream inhibition of NLRP3 inflammasome assembly or direct IL-18 neutralization successfully mitigate neuroinflammation. By either inhibiting NLRP3 inflammasome activation or directly neutralizing IL-18, these treatments shift the microglial toward a protective state, restrict histological damage, and significantly improve functional recovery.

Systemic bone loss is a frequent extraintestinal complication of inflammatory bowel disease (IBD) and can continue even when intestinal inflammation is clinically controlled. The steps linking gut inflammation to bone deterioration at distant sites are not fully defined. We found that interleukin-18 (IL-18) links intestinal inflammation to bone loss. In the gut, IL-18 supports mucosal repair and barrier maintenance. When circulating IL-18 remains elevated, it accumulates in bone-associated niches, shifts bone remodeling, and ultimately leads to bone loss. While IL-18 is a protective factor essential for intestinal repair and barrier homeostasis, its sustained systemic elevation leads to pathological accumulation in bone-associated niches, driving aberrant bone remodeling and bone loss. To address this challenge, we developed ExoBIP, a bone-targeted and microenvironment-actuated engineered exosome system. This platform enables site-specific IL-18 neutralization within inflamed bone tissues while preserving the physiological function of IL-18 in the gut. ExoBIP integrates the intrinsic pro-osteogenic properties of bone marrow mesenchymal stem cell derived exosomes with spatiotemporally controlled cytokine blockade, thereby simultaneously suppressing inflammation-driven bone resorption and supporting bone regeneration. In a chronic IBD-associated bone loss model, ExoBIP effectively restores bone mass, improves trabecular microarchitecture, and single-cell RNA sequencing showed that ExoBIP restores the marrow niche by increasing osteogenic cells and reducing inflammatory, cytotoxic CD8+ T cell programs. Collectively, this work establishes IL-18 as an actionable driver of IBD-induced bone loss and introduces a precision nanotherapeutic strategy for treating inflammation-induced skeletal complications, highlighting a generalizable paradigm for distal organ protection in chronic inflammatory diseases. [Display omitted] •Multi-omics analyses identify IL-18 as a key gut-bone mediator driving IBD-associated bone loss.•PBone targeted engineered exosomes deliver localized IL-18 blockade while promoting osteogenic repair.•ExoBIP restores bone mass, improves trabecular architecture, and shows biosafety in IBD-associated bone loss.