Immunoregulation by DC and T cells in psoriasis with probable immunotherapeutic approaches.

内容摘要

Psoriasis is a chronic, immune-mediated inflammatory disorder with systemic implications beyond its cutaneous manifestations. Its pathogenesis involves a complex interplay between genetic predisposition, environmental triggers, and immune dysregulation. The sustained crosstalk between dendritic cells (DCs) and T cells, which orchestrates the initiation and perpetuation of psoriatic inflammation. Plasmacytoid DCs, activated by nucleic acid-LL37 complexes, produce interferon-α that promotes myeloid DC maturation. These DCs secrete IL-12, IL-23, and TNF-α, driving differentiation of naïve T cells into Th1, Th17, and Th22 subsets. Effector T cells subsequently release cytokines such as IFN-γ, IL-17, and IL-22, which promote keratinocyte hyperproliferation, impaired differentiation, neutrophil recruitment, and angiogenesis. This DC-T cell axis forms a self-amplifying inflammatory loop that underpins disease chronicity. Conventional systemic agents, including methotrexate, cyclosporine, and retinoids, have demonstrated efficacy but are limited by nonspecific immunosuppression and significant toxicities. Advances in immunology have identified the IL-23/Th17 pathway as a pivotal therapeutic target, enabling the development of biologics and small-molecule inhibitors. Monoclonal antibodies targeting TNF-α, IL-12/23, IL-17, and IL-23 have revolutionized management, achieving high rates of sustained clearance with improved safety profiles. Additional strategies, such as PDE4 and JAK/STAT inhibitors, offer oral alternatives with targeted immunomodulation. Novel approaches, including tolerogenic DC therapy and neuroimmune modulation, hold promise for refining treatment and addressing disease heterogeneity. Effective immunotherapeutic strategies must therefore balance skin clearance with reduction of systemic inflammation and long-term comorbidity risk. Integrating mechanistic insights into DC-T cell interactions with emerging therapies provides a framework for personalized, safer, and more durable disease control. Psoriasis is a chronic inflammatory skin disorder mediated by complex interactions between dendritic cells (DCs), T cells, neutrophils, and macrophages. The immune dysregulation involves multiple cytokines and signaling pathways, leading to keratinocyte hyperproliferation, epidermal thickening, and sustained inflammation. Activated DCs release IL-1β, IL-6, IL-12, IL-15, IL-23, TNF-α, and IFN-α, driving differentiation of T helper subsets. Th1 cells secrete IFN-γ and TNF-α, inducing keratinocyte inflammation. Th17 cells produce IL-17A, IL-17F, and IL-22, which promote keratinocyte hyperproliferation, recruit neutrophils, and maintain chronic inflammation. Th22 cells secrete IL-22 and TNF-α, contributing to keratinocyte migration, while Th9 cells (IL-9, TNF-α) promote angiogenesis. Tc17 cells release IL-17A and IL-22, enhancing neutrophil infiltration, whereas γδ T cells amplify IL-17 and chemokine production, exacerbating inflammation. Targeted immunotherapies provide effective interventions by disrupting these cytokine-driven pathways. IL-17 blockers (secukinumab, ixekizumab, brodalumab) inhibit keratinocyte activation and neutrophil recruitment. IL-12/23 blockers (ustekinumab, guselkumab, risankizumab, tildrakizumab) suppress Th1 and Th17 responses. TNF-α inhibitors (etanercept, infliximab, adalimumab, certolizumab pegol) reduce systemic inflammation and keratinocyte activation. IL-22 inhibitors (fezakinumab) restore keratinocyte homeostasis and epidermal differentiation. PDE-4 inhibitors (apremilast) act via cAMP signaling to dampen NF-κB–mediated inflammation. JAK/STAT inhibitors block cytokine-driven immune responses, reducing T-cell activation and keratinocyte inflammation. Overall, psoriasis pathogenesis is closely linked to immune dysregulation, and modern biologics and small-molecule inhibitors offer targeted therapeutic approaches by blocking specific cytokine pathways, thereby improving disease management and patient outcomes.