The IL-23/IL-17 axis constitutes a critical signaling cascade governing inflammatory processes in psoriasis and PsA, with IL-23 serving as the primary upstream regulator and IL-17 acting as the central effector cytokine (80). Inhibitors toward this axis (such as bimekizumab, guselkumab, Secukinumab and ixekizumab), has achieved remarkable clinical efficacy (81).IL-23 initiates the pathogenic cascade by promoting the differentiation and expansion of IL-17-producing immune cells, particularly CD4+ T cells and γδT cells. While γδT cells producing IL-17 remain scarce in healthy individuals, they exhibit marked expansion in inflammatory milieus (82, 83). Notably, CD4-CD8-γδ+ IL-17-secreting γδT cells have been identified as essential mediators of enthesitis in PsA models (84, 85). Experimental evidence from A20+/– mice reveals systemic immune dysregulation characterized by elevated γδT cells, Gr-1-CD11b+ macrophages, and Gr-1+CD11b+ neutrophils in lymph nodes, mirroring immune alterations observed in human disease (71).

In A20-deficient murine models of imiquimod-induced inflammation, IL-23 orchestrates the recruitment of IL-17-producing γδT and CD4+ T cells to affected tissues through mechanisms modulated by the A20 protein (71). Molecular profiling demonstrates concurrent upregulation of IL-17A and IL-12/23p40 in cutaneous, lymphatic, and splenic tissues, paralleling findings in psoriasis patients with A20 haploinsufficiency (71). Therapeutic interventions reveal distinct roles within this axis: Complete resolution of ear swelling achieved through IL-12/23p40 neutralization contrasts with partial efficacy of IL-17 blockade, underscoring IL-23’s dominant regulatory position (71). In PsA models, IL-17A inhibition effectively prevents arthritis development, consistent with clinical responses observed in PsA therapeutics (39). The disproportionate elevation of serum IL-17 compared to synovial fluid levels suggests systemic rather than localized immune activation in PsA pathogenesis (86). Current evidence positions IL-17A as executing downstream inflammatory effects under IL-23 regulation, though precise mechanistic contributions to entheseal inflammation and bone remodeling require further elucidation. Emerging data from ZF7 murine models reinforce the therapeutic potential of IL-17 pathway modulation while highlighting residual disease components potentially mediated through alternative cytokine networks (39). These findings collectively establish the IL-23/IL-17 axis as a hierarchical signaling framework where IL-23 directs immune cell polarization and tissue homing, with IL-17 mediating subsequent effector responses in both cutaneous and articular manifestations of psoriasiform disease.

Unlike IL-17A, TNF is considered more relevant to arthritis than skin inflammation (87). Studies using A20-deficient murine models highlight TNF’s critical involvement (39). For instance, A20^myel-KO mice exhibit destructive polyarthritis accompanied by elevated systemic levels of TNF, IL-1β, IL-6, and MCP-1, alongside localized joint increases in TNF, IL-1β, IL-6, and IL-23 (72). Peritoneal macrophages from these mice constitutively secrete TNF and IL-6, both implicated in osteoclastogenesis (36, 72). Intriguingly, while IL-6 neutralization ameliorates arthritis, TNF blockade shows inconsistent therapeutic efficacy (72). To clarify TNF’s indispensability, TNF-deficient A20^ZF7/ZF7 mice were generated. Homozygous TNF deletion completely abolished arthritis development, whereas heterozygous deficiency prevented disease onset in most cases (39). These findings underscore TNF’s non-redundant role in arthritis pathogenesis, aligning with the clinical success of anti-TNF biologics in managing inflammatory arthropathies.

The synergistic interplay of TNF-α, IL-6, and IL-1β establishes a self-amplifying inflammatory loop central to arthritis progression. A2 is upregulated as a feedback mechanism to attenuate this cycle (88). Clinically, IL-6 is markedly elevated in the serum and synovial fluid of PsA patients, positioning it as a potential biomarker (89). However, therapeutic targeting of IL-6 with clazakizumab demonstrated limited efficacy in improving enthesitis, dactylitis, or joint inflammation, with no clear dose-response relationship, leading to discontinuation of clinical trials (90). IL-1β, another key mediator, is significantly upregulated in PsA patients and experimental models, where it exacerbates synovitis and bone erosion (91). Although Anakinra, an IL-1 receptor antagonist, has received regulatory approval for rheumatoid arthritis treatment, therapeutic targeting of IL-1β in psoriasis and PsA reveals heterogeneous clinical responses, suggesting context-dependent roles (92, 93). Collectively, these cytokines form an interdependent triad driving articular inflammation, yet their therapeutic targeting requires nuanced approaches to balance efficacy against complex immune redundancies.

Except for the classic cytokines discussed above, chemokines were also found critical in the development of PsA. Compared to RA and OA, cytokines such as CXCL10 and CCL20 (which can be induced by A20 deficiency), but not IL-17 and IL-23, are assumed PsA characteristic according to clinical studies (86, 94, 95). CCL20, primarily synthesized by epithelial cells including keratinocytes and intestinal cells, undergoes transcriptional regulation through IL-17 signaling while being modulated by MyD88 and TNF-α pathways (74, 96, 97). This chemokine specifically interacts with CCR6, a receptor expressed on Th17 cells, regulatory T cells (Tregs), macrophages, dendritic cell precursors, and innate lymphoid cells (ILCs) (98). The CCL20-CCR6 axis has been demonstrated crucial in the enthesitis of IL-23 minicircle DNA-induced murine PsA model (99). Furthermore, the synovial fluid of PsA patients exhibits higher CCL20 concentrations than serum, implying localized chemotactic activity that recruits CCR6+ immune cells to dermal and articular tissues, subsequently driving IL-17 production (86). CXCL10, an inflammatory chemokine predominantly secreted by monocytes and macrophages, engages CXCR3 receptors expressed on both immune and resident tissue cells (100). While elevated synovial CXCL10 levels position it as a potential PsA serum biomarker, clinical observations present conflicting temporal patterns – displaying transient increases followed by progressive declines in chronic phases (101–103). This chemokine’s dual presence in immune and structural cells suggests participation in both inflammatory infiltration and tissue remodeling processes (104). Emerging evidence implicates additional mediators including CCL2, CCL5, CXCL1, and S100A9, which are associated with A20 deficiency in experimental model, warranting further investigation into their synergistic or compensatory roles. The complex interplay between epithelial-derived chemokines and recruited immune effectors highlights potential therapeutic targets, though current understanding necessitates deeper exploration of spatiotemporal regulation and receptor-ligand dynamics in PsA microenvironments.

Aberrant bone resorption is a common pathological process in arthritis, where cytokines and chemokines play vital roles. Despite its rigid appearance, bone undergoes continuous remodeling mediated by a complex network of cytokines (105, 106). Pro-osteoclastogenic cytokines, including RANKL, TNF-α, IL-6, IL-1β, IL-17A, IL-23, IL-7, IL-8, IL-15, IL-11, IL-34, IL-21, CCL2, CXCL10, and CXCL12, drive osteoclast differentiation and bone resorption. Conversely, anti-osteoclastogenic cytokines such as IFNs, IL-4, IL-10, IL-3, IL-12, IL-27, and IL-33 counterbalance these processes to maintain skeletal homeostasis.

A20 deficiency disrupts this balance, predominantly upregulating pro-osteoclastogenic cytokines. TNF-α and CCL20 directly enhance osteoclastogenesis, while IL-17 and IL-1β indirectly promote bone resorption by elevating RANKL expression in osteoblasts and stromal cells (70, 107). Synergistic interactions between cytokines further amplify pathological responses: CXCL10 and RANKL mutually upregulate each other, exacerbating osteoclastogenesis in the presence of CD4+ T cells (104). Additionally, late-phase NF-κB response genes (e.g., Csf2, Il6, C3, Ccl5 and Mmp3), rather than the early phase genes, were found increased in A20-deficient cells and in the paws of pre-diseased A20^ZF7/ZF7 mice (39). This is consistent with the fact that the arthritis-correlated genes are mainly tanscribed in the late phase.

Adaptive immunity is essential in the development of PsA. A case-control study identifies an upregulated lymphocyte ratio (PLR) in patients with PsA compared to those with plaque psoriasis, implicating a role of lymphocytes in PsA (108). Although T and B cells were found unnecessary for the development of arthritis in A20^myel-KO mice, studies of A20^ZF7/ZF7 mice tells different (72). In A20^ZF7/ZF7 mice, T cells exhibit heightened activation and proliferation compared to wild-type counterparts, whereas B cells remain unaffected (39). Notably, lymphocyte-deficient A20^ZF7/ZF7 Rag1^KO mice failed to develop arthritis, underscoring the indispensable role of adaptive immune cells (39). However, B cell deficiency in A20^ZF7/ZF7 mice did not mitigate arthritis, indicating that T cells, but not B cells, are essential drivers of disease progression (39). Additionally, the lack of T cells protected mice with A20-deficient keratinocytes from PsA-like pathology (76). The contrasting outcomes across murine models underscore the complexity of immune interactions, reinforcing the need for targeted exploration of T cell-specific mechanisms in future therapeutic strategies.

The pathogenesis of arthritis in A20-deficient murine models is critically dependent on MyD88-mediated innate immune signaling. Experimental evidence demonstrates that peritoneal macrophages from A20^mye-KO mice and bone marrow-derived macrophages (BMDMs) from A20^ZF7/ZF7 mice exhibit hyperresponsiveness to lipopolysaccharide (LPS) stimulation (39, 72). This pathological response primarily engages the MyD88 adaptor protein rather than the Toll/IL-1R resistance (TIR) domain–containing adapter-inducing IFN-β (TRIF)-dependent pathway, as genetic ablation of MyD88 in both A20^myel-KO and A20^ZF7/ZF7 mice completely prevents arthritis development, while TRIF deletion fails to mitigate disease progression (39, 41, 72). The critical upstream receptors driving this process include TLR4 and IL-1R. Therapeutic TLR4 blockade effectively suppressed arthritis in A20^myel-KO mice (72). Complementary studies using A20^myel-KOIl1r^KO double-knockout mice reveal near-complete disease resolution, confirming the non-redundant roles of both TLR4 and IL-1R signaling pathways in arthritis pathogenesis (109).

MyD88-dependent signaling exerts its arthritogenic effects through both myeloid cells and non-myeloid cells. Notably, further knockout of MyD88 in synovial fibroblasts, inhibits arthritis caused by A20 myeloid knockout (41). Polykratis et al. delineated a critical IL-1β/MyD88 axis in SF activation, where macrophage-derived IL-1β stimulates SFs to produce metalloproteinases and inflammatory cytokines through MyD88 signaling (41, 72). This cellular crosstalk establishes a self-perpetuating inflammatory loop in joint tissues. In A20^KIKO mice, additional loss of MyD88 in keratinocytes, but not germline disruption of IFN receptors, also prevented the development of PsA-like disease, underscoring the broad, tissue-wide role of MyD88 (76).

The innate signaling pathways are intersected with adaptive immune responses, which is critically exemplified in dendritic cell (DC)-specific A20-deficient murine models. A20 exerts dual regulatory control over both MyD88-dependent and -independent signaling cascades within DCs (110). Genetic ablation of A20 in CD11c-Cre A20^fl/fl mice induces spontaneous DC activation, driving pathogenic Th1 and Th17 cell differentiation that underlies systemic inflammation (77). Paradoxically, in vitro stimulation of DCs from PsA patients with pathogenic stimuli and TLR ligands demonstrates suppressed pro-inflammatory cytokine release, despite concurrent upregulation of intracellular A20, SOCS3, and antimicrobial pathway components (111). This apparent discrepancy may reflect A20’s dual functionality in acute versus chronic inflammation, where its sustained expression in persistent disease states could stabilize negative feedback mechanisms to counterbalance inflammatory signaling.

The pathogenesis of PsA in A20-deficient models underscores the critical interplay between necroptosis and NLRP3 inflammasome activation. As stated above, A20 is pivotal in regulating NF-κB and TNFR1 signaling pathways. Experimental studies utilizing A20^myel-KO mice reveal that neither NF-κB inhibition via IKK2 deletion nor TNFR1 ablation fully prevents arthritis, suggesting redundant inflammatory pathways, such as TLR3/TLR4-TRIF or IFN receptor signaling, may compensate to sustain disease progression (41, 72). This highlights the complexity of inflammatory cascades in A20 deficiency and the need to explore alternative mechanisms driving joint pathology.

Central to arthritis development in these models is RIPK1-RIPK3-MLKL-mediated necroptosis. Genetic ablation of Ripk3 or Mlkl, or inhibition of RIPK1 kinase activity, significantly attenuates arthritis severity in A20^myel-KO mice. Notably, while RIPK3 or MLKL deletion suppresses IL-1β and IL-1α release from A20-deficient macrophages, loss of RIPK1 catalytic function does not, implying divergent roles for RIPK1 in necroptosis regulation (41). Emerging evidence suggests RIPK1 may exert non-catalytic scaffolding functions to propagate inflammation (112).

Concurrent with necroptosis, NLRP3 inflammasome hyperactivation emerges as a key driver of arthritis (41). A20^myel-KO mice exhibit elevated NLRP3 inflammasome activity in BMDMs, with genetic deletion of Nlrp3, Casp1/11, or ASC markedly reducing disease severity (109). Mechanistically, A20 deficiency amplifies both priming and activation phases of inflammasome signaling (58, 113). During priming, unchecked NF-κB activation upregulates NLRP3 and proIL-1β expression. In the activation phase, A20 loss lowers the threshold for NLRP3 oligomerization, facilitating IL-1β maturation. Studies indicate that A20’s zinc finger motifs, particularly ZnF4 and ZnF7, synergistically suppress inflammasome assembly, while NLRP3 activation reciprocally recruits A20 to inflammasomes, forming a negative feedback loop (39). Despite these regulatory mechanisms, inflammasome inhibition only partially alleviates arthritis, underscoring the contribution of inflammasome-independent pathways, including necroptosis, to disease pathogenesis.

The interplay between necroptosis and inflammasome activation in A20-deficient macrophages reveals a hierarchical relationship, with necroptosis predominating in driving tissue damage (41) (Figure 7). While A20’s ubiquitin-modifying functions are implicated in regulating both pathways, precise molecular mechanisms—such as its targeting of receptor complexes or inflammasome components—remain elusive (41). Intriguingly, RIPK3 and MLKL deletions not only block necroptosis but also reduce IL-1β levels, suggesting crosstalk between these pathways (41). This synergy may involve RIPK3-mediated NLRP3 activation or shared upstream regulators, though further studies are needed to delineate these interactions. As a consequence of the activation of cell death pathways, the released IL-1β subsequently stimulates synovial fibroblasts via IL-1R signaling, perpetuating synovitis.

In summary, A20 deficiency in PsA models unmasks a dual pathogenic axis: RIPK1-RIPK3-MLKL-dependent necroptosis and NLRP3 inflammasome hyperactivation. These pathways operate both independently and synergistically, with necroptosis serving as the primary driver of tissue injury and inflammasome activation amplifying IL-1β-mediated inflammation. Therapeutic strategies targeting both mechanisms—such as combined necroptosis inhibitors and NLRP3 antagonists—may offer enhanced efficacy in mitigating arthritis progression. However, unresolved questions persist regarding cell-type-specific contributions, the role of non-catalytic RIPK1 functions, and the temporal regulation of these pathways during disease evolution. Addressing these gaps will refine our understanding of PsA pathogenesis and guide precision therapeutic development.

Bone loss represents a critical pathological manifestation in PsA, occurring both systemically and locally. Systemic osteoporosis in PsA arises from excessive osteoclast activity, which disrupts bone remodeling homeostasis. Localized osteoclast hyperactivity contributes to periarticular bone erosion and irreversible joint deformities. A20 deficiency has been identified as a pivotal driver of accelerated osteoclastogenesis and associated osteoporosis. Experimental evidence from A20^mye-KO murine models demonstrates severe bone loss accompanied by elevated osteoclast-specific biomarkers and expanded populations of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) and CD115+CD117+ osteoclast precursors in splenic tissues (72).

In vitro analyses reveal enhanced osteoclast differentiation capacity in A20-deficient hematopoietic cells, with bone marrow-derived and peripheral blood leukocytes from A20^mye-KO mice forming osteoclasts exhibiting increased cell size, multinucleation frequency, and calcium phosphate resorptive activity compared to wild-type counterparts (36, 72). Cell-specific deletion studies further clarify A20’s direct regulatory role: osteoclast-restricted A20 knockout mice develop significant trabecular and cortical bone deterioration without systemic inflammation or arthritis, underscoring A20’s cell-autonomous function in bone metabolism (36).

Mechanistic investigations indicate A20 modulates osteoclast differentiation through multifaceted pathways, including suppression of necroptotic cell death, inhibition of Toll-like receptor (TLR) signaling cascades, and negative regulation of NF-κB activation (88, 114). Additionally, A20 exerts indirect control over osteoclastogenesis by modulating pro-inflammatory cytokine networks, particularly through downregulation of TNF-α, IL-1β, and IL-6 production, as stated above. These dual regulatory mechanisms position A20 as a critical molecular checkpoint in balancing bone resorption and formation, with its dysfunction contributing to pathological bone destruction in inflammatory arthropathies.

The JAK/STAT signaling pathway, an evolutionarily conserved cascade activated by cytokines, plays a critical role in immune regulation and has been implicated in the pathogenesis of A20 deficiency-related disorders (115, 116). Beyond its classical association with interferon (IFN) signaling, emerging evidence highlights its interaction with interleukin IL-17 and TNF signaling pathways (117). Clinically, inhibitors targeting this pathway, such as tofacitinib and upadacitinib, have demonstrated efficacy in managing psoriasis, PsA, and other autoimmune conditions, underscoring its therapeutic relevance (118–120).

Studies utilizing the A20^mye-KO murine model have elucidated the mechanistic link between myeloid-specific A20 deficiency and enthesitis (70). Myeloid A20 deficiency disrupts JAK/STAT signaling, leading to STAT1-driven inflammatory responses at entheseal sites (70). Notably, while prior research identified interactions between A20 and STAT3, the A20^mye-KO model revealed STAT1, rather than STAT3, as the primary mediator of enthesitis (69). Furthermore, the administration of tofacitinib, a jak inhibitor, alleviated enthesitis in mice (69). This divergence implicates the cell type-specific regulation of STAT proteins in inflammatory processes.