From Bed to Bench and Back: TNF-α, IL-23/IL-17A, and JAK-Dependent Inflammation in the Pathogenesis of Psoriatic Synovitis

Abstract

Psoriatic arthritis (PsA) is a chronic inflammatory immune-mediated disease with a burdensome impact on quality of life and substantial healthcare costs. To date, pharmacological interventions with different mechanisms of action, including conventional synthetic (cs), biological (b), and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs), have been proven efficacious, despite a relevant proportion of failures. The current approach in clinical practice and research is typically "predictive": the expected response is based on stratification according to clinical, imaging, and laboratory data, with a "heuristic" approach based on "trial and error". Several available therapeutic options target the TNF-α pathway, while others are directed against the IL-23/IL-17A axis. Janus kinase inhibitors (JAKis), instead, simultaneously block different pathways, endowing these drugs with a potentially "broad-spectrum" mechanism of action. It is not clear, however, whether targeting a specific pathway (e.g., TNF-α or the IL-23/IL-17 axis) could result in discordant effects over other approaches. In particular, in the case of "refractory to a treatment" patients, other pathways might be hyperactivated, with opposing, synergistic, or redundant biological significance. On the contrary, refractory states could be purely resistant to treatment as a whole. Since chronic synovitis is one of the primary targets of inflammation in PsA, synovial biomarkers could be useful in depicting specific biological characteristics of the inflammatory burden at the single-patient level, and despite not yet being implemented in clinical practice, these biomarkers might help in selecting the proper treatment. In this narrative review, we will provide an up-to-date overview of the knowledge in the field of psoriatic synovitis regarding studies investigating the relationships among different activated proinflammatory processes suitable for targeting by different available drugs. The final objective is to clarify the state of the art in the field of personalized medicine for psoriatic disease, aiming at moving beyond the current treatment schedules toward a patient-centered approach.

Keywords: IL-23/IL-17 axis; JAK/STAT pathway; TNF-alfa; personalized medicine; psoriatic arthritis; synovial biopsy; synovial histopathology; targeted therapies.

FIGURE 1

Schematic representation of the main pathogenic processes driving PsA development and chronicity. PsA is a heterogeneous chronic disease, with skin, entheseal, and synovial tissue involvement occurring in different proportions across patients under genetic and environmental triggers. For skin manifestations, activated dendritic cells secrete predominantly IL-23, which in turn induces the differentiation of naïve T cells into Th17 cells. IL-17 is responsible for keratinocyte activation and subsequent perpetuation of skin inflammation. At the entheseal level, resident and infiltrating entheseal myeloid cells produce IL-23, which is responsible for lymphocyte activation and the inflammatory response, as well as bone damage. Psoriatic synovitis, on the contrary, is characterized by tortuous and immature neoangiogenesis, with antigen presentation by dendritic cells and macrophages leading to lymphocyte activation. As a result, the synovial inflammatory infiltrate is rich in activated lymphocytes, mast cells, and macrophages. Polyfunctional T cells are responsible for the production of several types of proinflammatory cytokines (e.g., TNF-α, IL-17A, GM-CSF, and IFN-γ) in the synovial membrane and synovial fluid. The proinflammatory cytokine milieu further activates fibroblast-like synoviocytes, chondrocytes, osteoblasts, and osteoclasts, resulting in bone damage.

FIGURE 2

Downstream signal transduction mechanisms following TNF-α, IL-17A, or JAK/STAT-coupled receptor activation. Type I and II cytokines (e.g., IL-23, IL-22, IL-6, and type I, II, and III IFNs) bind JAK/STAT-associated receptors. JAK proteins are associated with the cytoplasmic domain of these receptors, and when cytokines bind to the receptor, JAKs undergo autophosphorylation and phosphorylate other JAKs. STATs recognize JAKs, bind their cognate receptors and become phosphorylated by JAKs. STATs then translocate to the nucleus, bind DNA and activate the transcription of target genes for the interferon response, proinflammatory mediator production, and ECM degradation. IL-17A binds IL-17R, a transmembrane heterodimer of IL17RA and IL-17RC. This binding induces Act-1 activation, which in turn activates TRAF6 and, accordingly, NF-kB. NF-kB migrates to the nucleus and induces target gene transcription. TNF-α, either in its soluble or transmembrane form, binds TNFR1 or TNFR2. After binding, in the classical proinflammatory axis induced by TNF-α-dependent cellular activation, TAK1 engages NEMO. NEMO activation results in the phosphorylation of specific serine residues in inhibitory proteins of NF-κB (IκBs) by IKK-1 and IKK-2, leading to IκB polyubiquitination and proteasome-dependent degradation. This process releases NF-κB proteins, which translocate to the nucleus and induce target gene transcription. Taken together, these mechanisms result in an interferon response, proinflammatory chemokine and cytokine release, and extracellular matrix degradation. Abbreviations: TNF-α, tumor necrosis factor-alpha; IL, interleukin; JAK/STAT, Janus Kinase/signal transducer and activator of transcription; ECM, extracellular matrix; IL-17R, IL-17 Receptor; Act1, NF-kappa-B activator 1; TRAF6, TNFR-associated factor 6; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; TNFR, tumor necrosis factor-alpha receptor; TAK1, transforming growth factor-alpha-activated kinase 1; NEMO, NF-κB essential modulator; IKK, inhibitor of IκB kinase; IκBs, inhibitory proteins of NF-κB. This image was created with © BioRender 2021.