| Mechanistic domain | Key molecules / pathways | Principal cell types | Mechanistic details in AOSD | Clinical / translational relevance |
|---|---|---|---|---|
| Core inflammatory program | IL-1β, IL-6, IL-18, TNF-α, IFN-γ | Monocytes/macrophages, neutrophils, T cells | AOSD is consistently described as a systemic autoinflammatory disease driven by dysregulated inflammation and a “cytokine storm,” with excessive production of IL-1, IL-6, IL-18, TNF-α, and IFN-γ; these cytokines link systemic fever/rash phases with severe hyperinflammatory complications such as MAS | Explains rationale for IL-1 and IL-6 blockade; IL-18 is an emerging biomarker and therapeutic target |
| Innate immune predominance | Innate immune activation, PRRs, inflammasome signaling | Monocytes/macrophages, neutrophils | Reviews describe AOSD as predominantly innate-immune driven, although not exclusively; activation of monocyte-derived cells and neutrophils is central to initiation and amplification of inflammation | Supports classification of AOSD as an autoinflammatory disorder and prioritization of innate-immune biomarkers |
| Monocyte/macrophage activation | IFN-γ stimulation; PAMP/DAMP-PRR axis; NLRP3 inflammasome; caspase-1 | Monocytes, macrophages | Monocyte/macrophage activation is a central upstream event. Stimulation by IFN-γ, PAMPs/DAMPs, and NET-derived DNA activates NLRP3 inflammasomes, leading to caspase-1 activation and cleavage of pro-IL-1β and pro-IL-18 into mature cytokines | Provides mechanistic basis for inflammasome-centered models of disease and for targeting IL-1/IL-18 pathways |
| IL-18 axis | IL-18, IL-18BP, free IL-18 | Macrophages, monocytes, NK/T-cell axis | IL-18 is one of the most distinctive cytokines in AOSD and MAS; imbalance between IL-18 and its natural inhibitor IL-18BP increases biologically active free IL-18, promoting systemic inflammation and correlating with disease activity | Useful for diagnosis, disease monitoring, MAS risk assessment, and investigational IL-18BP therapy |
| TLR-DAMP signaling | TLRs, endogenous ligands/DAMPs, S100 proteins | Innate immune cells, especially monocytes/macrophages and neutrophils | Endogenous danger signals interact with Toll-like receptors to induce sterile inflammation; altered TLR-DAMP signaling is proposed to initiate and/or perpetuate AOSD inflammation and may contribute to susceptibility and severity | Positions DAMPs/TLRs as biomarker candidates and possible upstream therapeutic targets |
| NET-driven amplification | Neutrophil extracellular traps (NETs), DNA sensing pathways | Neutrophils, monocytes | NETs are increased in AOSD and act as inflammatory amplifiers. NET-derived DNA stimulates monocytes, upregulates DNA sensors, expands inflammatory intermediate monocytes, and activates inflammasome pathways; DNase I can abrogate these effects experimentally | Suggests therapeutic relevance of NET inhibition or DNA clearance strategies, especially in MAS-prone disease |
| Ferritin as pathogenic mediator | Ferritin, Msr1, PAD4, neutrophil elastase, ROS | Neutrophils, liver-infiltrating innate cells | Ferritin is not only a biomarker but can act pathogenically: ferritin binds/scavenger receptor Msr1 on neutrophils, promoting ROS-, PAD4-, and neutrophil elastase-dependent NET formation, cytokine storm, and tissue inflammation | Reframes hyperferritinemia as a driver rather than a passive marker; highlights Msr1/NETs as novel targets |
| Intermediate monocyte expansion in MAS | CD14^bright^CD16+ intermediate monocytes, CD163, CD80, CD86, HLA-DR, CCL8, CXCL10 | Intermediate monocytes, macrophage lineage cells | Active AOSD shows expansion of intermediate monocytes with activated phenotype and increased phagocytic/cytokine capacity; these cells are further enriched in AOSD-MAS and associated with CXCL10/CCL8 signatures | Helps explain transition from active AOSD to MAS and identifies CXCL10 plus monocyte phenotyping as candidate biomarkers |
| Neutrophil–monocyte chemokine axis | CCL2–CCR2 axis | Neutrophils, monocytes | NET stimulation enhances CCR2 expression and secretion, while serum CCL2 is elevated in AOSD; the CCL2–CCR2 axis likely promotes recruitment and activation of inflammatory monocyte-derived cells | Supports a chemokine-based model of leukocyte trafficking and inflammatory amplification |
| Adaptive immune contribution | Th1 cells, Th17 cells, Tregs, activated T cells, soluble IL-2 receptor | CD4+ T cells, regulatory T cells | Although AOSD is mainly autoinflammatory, adaptive immunity contributes meaningfully: Th1/Th17 responses are increased, Treg frequencies are reduced, and elevated soluble IL-2 receptor suggests T-cell activation/proliferation | Supports the view that AOSD lies at the crossroads of autoinflammation and autoimmunity |
| NK-cell dysregulation | Reduced NK-cell activation / dysfunction | NK cells | Reviews note low activation of NK cells in the setting of hyperactive macrophages/neutrophils and T-cell abnormalities, consistent with defective cytotoxic immune regulation in hyperinflammatory states | Mechanistically relevant to MAS susceptibility and uncontrolled cytokine activation |
| Skin inflammation mechanisms | IL-1β, IFN-γ, keratinocyte apoptosis/caspase pathways | Keratinocytes, dermal neutrophils, T cells | In atypical persistent eruptions, IL-1β and IFN-γ are implicated in necrotic keratinocyte pathology; early lesions show neutrophilic perivascular dermal infiltrates, while later lesions may reflect deeper cytokine-driven epidermal injury | Connects cutaneous phenotypes to cytokine endotypes and may help distinguish disease subsets |
| Cytokine storm phenotype | Hyperferritinemia, IL-1β, IL-6, IL-18, TNF-α, IFN-γ | Multicellular innate/adaptive network | The severe end of AOSD biology is an uncontrolled cytokine storm integrating innate activation, NETs, inflammasome signaling, and downstream adaptive responses, culminating in multiorgan dysfunction and MAS | Explains why early targeted therapy may alter trajectory and why biomarker-guided stratification is important |
| mTOR signaling | mTORC1 and downstream inflammatory integration | Immune cells, especially neutrophils/monocytes | Recent Still disease literature increasingly identifies mTORC1 as an integration hub converging cytokine signals and sustaining inflammatory programs, though direct AOSD-specific human evidence remains emerging rather than definitive | Represents a promising pathway for refractory disease and a rationale for JAK/mTOR-related experimental strategies |
| Interferon pathways | Type II IFN (IFN-γ); emerging type I IFN signatures | Macrophages, T cells, innate effector cells | IFN-γ is a major activator of monocyte/macrophage inflammatory programs and contributes to MAS-like pathology; newer literature suggests interferon-related signatures may help define severe disease biology | Relevant to refractory hyperinflammation and to emerging anti-IFN-directed approaches |
| Regulatory/autophagy checkpoint | PLAC8, autophagy, suppression of pro-IL-1β and pro-IL-18 synthesis | Monocytes | PLAC8 is increased in monocytes during active AOSD and correlates with CRP, ferritin, IL-1β, and IL-18; experimentally, PLAC8 can suppress pro-IL-1β/pro-IL-18 synthesis via enhanced autophagy, suggesting a compensatory regulatory mechanism | Indicates that failed counter-regulation may contribute to disease persistence and suggests new biomarker/target possibilities |
| Still disease continuum | Shared inflammatory programs with systemic JIA | Overlapping innate/adaptive immune cell networks | AOSD and systemic JIA share major inflammatory modules including IL-1/IL-18 excess, hyperferritinemia, innate immune activation, and MAS susceptibility, supporting a unified Still disease spectrum concept | Important for extrapolating pediatric/adult mechanistic insights and therapeutic strategies |


*Table: This table summarizes the main cytokines, immune cells, and molecular pathways implicated in Adult-Onset Still Disease pathophysiology. It is useful for connecting biomarkers and clinical phenotypes such as systemic inflammation and macrophage activation syndrome to underlying mechanisms.*